JPS6038384A - Novel synergistine and manufacture - Google Patents

Abstract

The invention provides new synergistine derivatives of the formula: <IMAGE> (I) in which Y=H or N(CH3)2 and R represents: (a) H or OH, (b) a radical of the formula NR1R2, in which R1 and R2=H, phenyl or pyridyl (optionally substituted by dialkylamino (1 to 4 C), alkyl (1 to 10 C) [optionally substituted by OH, SH, COOH, anilino, or alkylamino or dialkylamino of which at least one of the alkyl parts is substituted by OH, SH, COOH or anilino 9 , alkenyl (3 or 4 C) or alkynyl (3 or 4 C), or alternatively R1 and R2 together form a heterocycle optionally containing another heteroatom such as O, S or N (optionally substituted by alkyl), or (c) a halogen atom, a trimethylsilyloxy or dialkylphosphoryloxy radical or a radical -OSO2R3 or -OCOR4, R3 being alkyl, trifluoromethyl, trichloromethyl or optionally substituted phenyl and R4 being defined in the same way as R3 or being an acylalkyl, alkoxycarbonylalkyl or alkoxy radical, and also their salts and their preparation. These products are useful as intermediates in the synthesis of anti-bacterial synergistine derivatives.

Description

[Detailed description of the invention]

Pristinamycin (prisLinamycin) and virginiamycin (virHiniamycin)
is a well-known synercystin (synergiSl, 1n
e) is a derivative: J * Preu-d'l+omm
e-murmur IIull, Soc, claim, Fr...
2.585-9-ri1 (1!368). The present invention provides intermediates for the preparation of therapeutically active synergystin derivatives and novel synergystin derivatives of formula 17 useful, and salts thereof, if present. In formula (T), Y is a hydrogen atom or dimethylamine 7
represents a group, and R is a) a hydrogen atom or a hydroxyl group, 1]) Formula -I\I (II)\1(2 In the formula, R1 and R3 are the same or different, and hydrogen h; (γ , phenyl or pyrinol groups optionally substituted (with each alkyl L (or linear alkylamino containing 1 to 4 carbon atoms in the branched chain)), optionally (human r7 ``may be substituted (with an alkylamino or dialkylamino group which is itself substituted with a hydroxyl, mercapto, carboxyl or anilino group or with at least one alkyl or anilino group) , irr tJ''1 or b. representing an alkyl group containing 1 to 10 carbon atoms in the branched chain, an alkenyl group of 3 or 4 carbon atoms or an alkynyl group of 3 or 4 carbon atoms, or also R1
and r together with the nitrogen atoms to which they bond = 11
- (optionally substituted with an alkyl group)
If! ! -・Terror l+'', i rFor example, oxygen, sulfur [7 or nitrogen may optionally be included or (i
i4t7'l or C) halogen radical r゛, trimethylsilyloxy or noalkylphosphoryloxy group, or formula % formula % () )), where 1 (, is alkyl, tri- Fluoromethyl t>L
, <kl is a trichloromethyl group or a phenyl group optionally substituted with a halogen atom or an alkyl or nitro group, and R, + is the same as 1 or 3, or alkylcarbonyl, methyl, 2 -alkylcarbonylethyl, alfkylcarbonylmethyl,
Represents 2-alfkidicarbonylmethyl or an alkoxy group. represents the basis of 12- It is understood that the alkyl groups and alkyl moieties mentioned above or below are linear or branched (unless otherwise specified) and each contain from 1 to 4 carbon atoms. If the radical R represents a halogen atom, this can be a chlorine or a bromine atom. The compound of formula (T) in which R is other than the group of formula (11) has 2
Two isomeric forms exist and these isomers and mixtures thereof are also within the scope of this invention. According to a feature of the invention, the compounds of formula (I) are of the formula (wherein
1<1 and R2 each represent 1 to 4 carbon atoms. Xl and x2 are are the same or different, and include an alkoxy group or -N R, I'
< 2 and 13- represents a substituted amine group as defined in the same way Y, ) represents a compound of the formula r).wherein )' is defined in 1.
7; Let )′ is defined by the force equation, and R is 1<
1 and 1ri1. This reaction is followed, if appropriate, by forming a compound of formula (1) representing a radical of formula (II) with the meaning given above for formula (III); Reacting with an alkali metal borohydride in the presence of a strong organic acid to give a product of formula (1) in which R represents a hydrogen atom, or 2) products of formula (1) in which 1?'1 and 1' 2 is defined for formula (Ill) (also ai), with the meanings given above for R1 and R2, excluding taste), resulting in trans-enamination (l ranStq+am i na 1. io
n) to produce a formula (T) in which Y is defined in 111 and 1 represents a group of formula (II) in which R1 and R2 are defined in the same manner as R' and 11' above. () to give a product of formula (), which is then hydrolyzed to give a product of formula, and then optionally a halogenating agent or phosphoryloxy group or group -OSO2R3 or 10C0R4, and X represents a halogen atom, by reacting with a compound of l)R is defined by 2C) 17- The formula ([ ) is converted to the product of The product of general formula (bi) is replaced by X, and/or X2 is
/! Was it done? When prepared using a reactant of formula (Lll) representing Mino J11,
Substituted amino groups or groups present in the molecule -NR. [It is preferable to choose so that it is the same as <2. t
-Butoxybis(dimethylami7)methane is preferably used. In fact, the reaction between the compound of formula 1 (Ill) and the compound of formula (H) is as follows:
- dichloroethane) or an amide (e.g. dimethylformamide) at a temperature of 0 to 25°C, preferably 2+1'
It is generally carried out at a temperature on the order of C. The reaction of an alkali metal borohydride with a compound of general formula (■゛) is generally carried out in an organic solvent such as an ether (eg, tetrahydrofuran) or an alcohol (eg, isopropanol) using sodium borohydride! or using cyanogen borohydride in the presence of a strong organic acid such as trifluoro-18-acetic acid ("C7").
and the reflux temperature of the reaction mixture. The reaction is preferably carried out over a range of about 2 rl'C. The reaction between the amine of 2〇・“) and the compound of the general formula (r゛) is generally carried out using a solvent such as R11 acid or alfur (
e.g. 'ethanol) at a temperature of () ~ 25 °C, br
It is carried out at a temperature of approximately 20°C. Hydrolysis of a compound of formula (1') to produce a compound of formula (vl) is generally carried out in a dilute acid at a temperature of the order of 2 fl"C. A (1,IN solution of hydrochloric acid may be used). Advantageously, by reacting a halogenating agent with a sinernstine derivative of formula (vl), formula (1) in which R is a halogenating agent
For the preparation of products of phosphorus, halogen derivatives of phosphorus, in particular halogen/sulfite triaryl compounds, or if R is also a chlorine atom, dichlorotriphenylphosphorane or canakyl-1-lichlorophosphorane. , or when R is a bromine atom, it is advantageous to include catekyltribromophosporane as the j-position. , two anti-L; ; is generally carried out in a chlorinated solvent such as methylene chloride at a temperature of -207+, +2 (1'C). The fit of formula (\]11) n Synergistin inducement of formula (~11) 11. and anti-II., 11- place punishment,
It is preferable to use methacrylate 4, which is a chlorine or bromine atom. This anti-1. M;1. j Generally I! In other solvents such as methylene chloride, there is an acid acceptor such as 1-ethylamine.
Bicarbonate or bicarbonate such as "17i-ij: Acid I
Ryuuno or potassium bicarbonate and no IE'jLi
The reaction temperature is generally −2()・+2 I)'(''). The compound of formula (Ill) is It, CIueIll by Rredereck et al. l(+・r, I fl I
, 4 1 (1968), CI+em, Ber.
,-]-011,'! ! I 5 i'i (1ri
68) and CI+em, Ber,] (in '1,:
Gon 2! (1 7 g) Prepared by the method described. You can do something like two. When the compound IJ)' of formula (1 to l) represents calimethylamide 7, it is pristinamycin (prisl, inamycin) TA, a known synergystin derivative, and when )' represents hydrogen, it is virginiamycin S. The compound of formula (T) is a compound of the formula (T), in which Y represents a hydrogen atom or 1 dimethylamino group, and either Aids or R6 each represents a hydrogen atom,
and R1 is a pyrrolidin-3-yl21-thiono-1(), Igopiperidin-3-ylthio, or a pyrrolidin-1-ylthio group (these groups are
tili 11. ', r alkyl tatami 11, may be substituted)! , :J or alternatively R4 is substituted with one or two hydroxysulfonyl, alkylamino or dialkylamino groups or piperazino (optionally substituted with an alkyl group), morpholif, thiomorpholif, Piperin-7, pyrrolidin-1-yl, piperidin-2-yl, piperidin-3-yl or piperidin-1-yliso and pyrrolinone-2
- Iru also [2 kukepi]

) one or two-yl selected from phosphorus-3-yl (these latter five rings may be substituted with a nitrogen atom by an alkyl group)
), or rl>r<, and r<6 together form a valence bond, and IL represents pyrrolicin-3-ylami7
, piperinon-3-ylamino or pyrrolidin-3-ylamino, pyrrolidin-; represents a 1-1-ylthio radical (these radicals may optionally be substituted on the nitrogen atom of the ring by an alkyl group) or also represents one or two hydroxysulfonyl, alkylamino, dialkyl Amino, trialkylammonio or imigsol-toyl or imidazol-5
-yl group, or piperidine (optionally substituted with an alkyl group), morpholino, thiomorpholino, piperidino, pyrrolinon-1-yl, piperidin-2-yl, piperidin-3-yl or piperidin-4 -yl and pyrrolidin-2-yl or pyrrolidin-3-yl (the latter two rings optionally being substituted on the nitrogen atom by an alkyl group); For the preparation of therapeutically oily synergistic derivatives of alkylamino, alkoxy or alkylthiono (1) substituted with
・j, in which the general formula (v)il)i2j'; and the alkyl group and the alkyl moiety contain carbon atoms γ1...5Ill111,
In order to obtain a therapeutically active 2ml+) compound, it is understood that the straight-chain or IJun (01''1 form is J+).
8. The compound of the present invention 17 can be used in the following method (=
p: 1. To prepare a compound of the formula (Vlm) defined by the symbol or 1-indication A), the formula % formula % () where for R', lj, R, "2" A compound having the definition given in A) is reacted with a compound of formula A) defined by Y or 1- and R representing a hydrogen atom. This reaction is carried out in a chlorinated solvent such as a 24- alcohol such as methanol or chloroform, or a mixture of these solvents, between (1'C and the reflux temperature of the reaction mixture). 2. R4 is pyrrolidin-3-yloxy, piperidin-3-yloxy, preferably piperidin-.1-yloxy or an alkoxy group [optionally substituted as defined in B). To prepare a compound of formula (Vll+), the symbol is defined in B) above, except that R4 is pyrrolinon-3-yloxy,
R1 except that it cannot represent piperidin-3-yloxy or piperidin-4-yloxy or an alkoxy group, optionally substituted as defined in B).
When a compound having the definition given in B) above is reacted with a compound 25- of formula (1), where R is defined in (1)), the second reaction is - The shell is placed in an acidic substance (e.g. acetic acid), with or without a solvent, at a temperature of about 0 to so'c opening, lr or fl ℃, to an appropriate temperature. If so, it is carried out in the presence of trifluoroacetic acid as catalyst h1. The solvent used is gothyl (e.g. tetrahydrofuran)
, alcohol (e.g. ethanol) or chlorinated]
solvent (e.g. methylene chloride or chloroform)
It may be. 3. In order to prepare a compound of the formula (v■■1) defined by the symbol 1(), the formula %formula%() is used. A compound of formula (I), given the definition given in B), is reacted with a compound of formula (I) as defined in C). This reaction is generally carried out in an organic solvent such as an ether (e.g. alcohol (e.g. ethanol)
or an alkali metal hydroxide or alkali metal alcoholade, such as sodium ethylate or potassium L.
- carried out in the presence of a butyrad exobase. R4 is a substituted alkoxy group or heterocyclyloxy (h
eLerocyclyloxy) group, the reaction is carried out in a neutral medium at a temperature of ().
It can also be carried out under any of the same conditions as mentioned above for the reaction of the compound of VI) with the compound of formula (XIV). In order to prepare therapeutically active compounds of formula (VIll), if the group in general formula (IX), (X) or (XI) contains a secondary amine group which can inhibit the reaction, This must be protected with a protecting group before reacting with the compound of formula (r), and then this protecting group must be removed after the reaction. It is commonly used to protect secondary amine groups without affecting the rest of the molecule,
And after that, it will be removed.
The locking method can be used in this way. Particular preference is given to using (-) and (-) as protecting groups. This compound can then be removed using an alkali metal bicarbonate, such as bicarbonate, and sinernostin, which can be removed using an aqueous solution of potassium bicarbonate. Ial+I+Vlococcu:;), consecutive U
Bacteriotrophic genus (S t, repl,. (:OCf', Ll!i), Lungcocoon genus (l'neum)
ococcus) or enterobacterium fW genus ([ri1 mountain, t.
CO Shin: u! i)] Durham positive bacteria and
genus Neisseria (llac+nml+11yama+s), genus Neisseria gonorrhoeae (
Gonoc. (:C1l!i) Meningofutchus
[ingococcus] grano, which is used to treat infections caused by 1'l bacteria. Shikarna mumbles the known synergistin 1f water f'llv, quality f: dissolution ia 1.
Is it possible, therefore, to be administered only orally in the form of encapsulated, coated tablets or regular tablets? It has the disadvantage of Due to this insolubility, previously known dinergystins cannot be used if the patient is unable to tolerate them; this is especially the case in pediatric and intensive care settings, whereas their production The broad spectrum of activity of the products gives them valuable applicability in many situations, such as in cases of coma (comat, ose septicaemia). They have considerable advantages in that they can be dissolved in water at low concentrations, while retaining the activity of synergystin in the typical range. Staphylococcus aureus (Sta) at a concentration of
phylococcus aureus Sm1th)
There is in vitro activity against. Their toxicity is generally low. Their LDSo values are generally greater than 300 mg/kg when administered subcutaneously to mice. Compounds of formula (T) and also therapeutically active formula (v)
The product can be purified by conventional methods, such as crystallization, chromatography and, if necessary, subsequent extraction in acidic or basic media. For those skilled in the art who are familiar with the sensitivity of cinerustin in alkaline media, the term U basic medium J refers to the parent substance as its acid 1. A medium that is just enough alkaline to cause a 11% drop, i.e. 1) ■1 value of 7.
It is clear that this is understood to mean not more than 5 to 8 media. If the novel compounds of formula (T) exist in isomeric forms, these can be separated, for example, by high performance liquid chromatography. The compound of formula (1) can also be converted into an addition salt, if desired, by reaction with an acid in an organic solvent such as an alcohol, ketone, ester or chlorinated solvent. Concentrate the solution if appropriate1. After that, the salt will precipitate; filter or decant this! )To separate. Furthermore, the acid addition salt cannot be obtained in the form of an aqueous solution by adding an aqueous solution of the corresponding acid to the compound of formula (T). The 30-compound of formula (1) in which R represents a group containing a carboxyl group can be converted to a metal salt or nitrogen base in the same manner as in Section 2 for acid addition salts, except that the acid is changed to a metal hydroxide or nitrogen base. (can be converted into addition salts. Examples of salts that may be mentioned are addition salts with mineral acids, such as hydrochlorides, hydrochlorides, hydroiodides, sulfates, nitrates and phosphates, Preferably, salts with organic acids, such as 11-acid, bucopionate, succinate, maleate, hexamarate, methanesulfonate, 1)-toluenesulfonate, isothionate, etc. - lifluoroacetates and oxalates, or substituted derivatives of these compounds, and salts with alkali or supra-alkali metals such as potassium, sodium, lithium and magnesium, and also organic nitrogen bases such as dimethylamine, diethylamine, diisopropylamine, Dicyclohexylamine, N
-ethylpiperidine, N-methylmorpholine and ethyl 7
-Addition salts with amines. Of particular value are those in which Y is defined as ``-'' and 31- represents a hydrogen atom r, a HylS'roxyl group, or , phenyl optionally substituted with 7 dialkylamino groups, Ff
If (vitroxyl, mercapto, carboxyl,
Pyridyl is also cy, < is anilino group, or alkyl is substituted with human rJxyl (negative 1, alkylamino or carbon atom -r3 or -N It , R2 representing four alkenyl groups, are compounds of formula (I). Among the stiff groups, the following are of further particular value: 5δ-dimethyl “?mino” methylene pristinamycin)
A Σ) δ-dimethino [ami7methylenevirsoniamycin S 5δ-nona1/]/pristinamycin IA5δ-human rj gysymethylenepristinamycin A 32- 5δ-methylenevirginiamycin S The following products are also valuable: 5-Trifluoroacetoxymethylenepristinamycin 85-Trifluoroacetoxymethylenevilsoniamycin S The following examples illustrate the invention. Application examples show that the products of the invention can be used with the therapeutically active formula (vi
This shows whether it can be converted to a compound of m. The NMR spectra of the products described in the Examples and Application Examples reflect the general features common to all products as well as specific to each product according to the variable substituents in the general formulas (I) and (Vll+). has certain characteristics. Example 1
In (), the assignment of all protons in the molecule is obtained; in the subsequent Examples and Application Examples (), only the specific features due to the substituents that can be changed are described. is shown according to the following basic formula, and J, O, AN
C Eur, J, B ioc by TEUNIS et al.
hem, , 5-33-);,;-1! -1! 〇＼ −:+4− I'll shown in the numbering l + eri ++ 8) inscribed with + (+≦)'75)) J: j). All spectra are in deuterium-chloroform at 250
M)→Z; chemical shifts are expressed in ppm relative to the signal of tetramethylsilane. The abbreviations used below are as follows: S = single line d - doublet t = -H multiplet ll1t - multiplet Ij p = unresolved peak
peaks) dd-double line knee lane dt-I',, double line double lineddd-double line 12Φ line double linedddd-7ff double line double line double line double line In the doublet Examples 2 to 24 and also in the application examples, the following are respectively given in parentheses: chemical shift, shape of the jig pull, integral value (number of protons, percentage of isomers, if appropriate).
and proton attribution. In the following examples and application examples, [Flash 1
(“eye ash”) chromatography is W. C, 5TIL+-1M, KAHN and A, MITRA
[J, Oro, O1+em,, 43.2923
(1978)], using short chromatography columns and operating with silica with a particle size of 40-63/7111 under moderate pressure (50 kPa). This can be understood to mean the shaft manufacturing technology. Example 1 t-Butoxybis(dimethylamino)methane (2300
0) was added to a solution of pristinamycin IA (46(1)) in 1,2-dichloroethane (460 CC); the resulting solution was stirred for 18 hours at a temperature around 20°C. The reaction mixture was dissolved in methylene chloride ( 11) and then washed three times (31 times in total) with a 0° 4% aqueous solution of ammonium chloride. The organic phase was dried over magnesium sulfate, filtered, and the filtrate was diluted under reduced pressure with ( 2.7kPa) was concentrated to dryness at 30°C.The resulting residue was soaked in distilled water (60Qc
Disintegration with c): The mixture was filtered, the filtrate was dried and concentrated to dryness at 20° C. under reduced pressure (2,7 kPa). This produced crude 56-dimethylaminomethyllenpristinamycin 1,4 (41o) in the form of a beige powder. The product was of sufficient quality for use as is in subsequent syntheses. However, it was possible to purify this 37- product by the following method: crude 56-dimethylamino methylene pristine mycin 1
, 4 (23,5 g) was chromatographed on a "Flash" Chroma 1 Hegrano, E during elution).
If i;tI:] ]I-]form/methanol 9
8/2 capacity > r. Fractions 16-25 were combined and concentrated to dryness under reduced pressure (2,7 kPa) at 30°C. This produced 5δ-dimethylaminomethylene prisdinamycin IA (12 g) in the form of a white powder that melted at about 195°C. -:38- Example 2 Virginiamycin s (2(+) and'bis(dimethylamino)l-:/'1,4-dimethane (10c
c) The same method as described in Example 1 was used except for the color effluent: 1-flash chromatography. /2 volume φ) 1 and purified under reduced pressure (2.7 kP
In step a), 30'Cr fractions 9 to 12 were dried to dryness.11IelL56-dimethylaminomethylenevirginiamycin S (0.8 g) was obtained in the form of a yellow powder melting at about 175°C. N M 11 spectrum: 0, 9 (+beat; 41-1: 2 γ+5β2
)3,05 (S; 6H: -CH-N (cHs
) 2) 3.65 (d: 1t-1:5ε2)4.
85(d: IH:5ε1):3,1! i (dd; 'I N : 5α〉7
．． 1() to −7,40(llp: aromatic proton +=
CIIN) 40-7, 70 (dd: IH: 1'H&) Example 3 4N ethanolic solution of gaseous ammonia (1Qcc)
was slowly added to a solution of 56-dimedylaminomethylenepristinamycin 14 (1,84(+)) in acetic acid (20 cc).
Stir for an hour and then a saturated aqueous solution of sodium bicarbonate (20
0CC). The resulting suspension was diluted with methylene chloride three times (3\00 in total).
00) Extraction; the organic phases are combined, dried over magnesium sulfate, filtered and the filtrate is extracted under reduced pressure (2,7 kPa
) and concentrated to dryness at 30°C. The resulting residue was purified by "flash" chromatography [eluent: chloroform/methanol (92/8 vol)]. Fraction 11 ~ at 30 °C under reduced pressure (2,7 kPa)
By concentrating 13 to dryness, 5δ-aminomethylene pristinamycin 1,4 (1,3(+)) was obtained in the form of a beige powder that melts at about 190°C. NM R spectrum: 0.7-'1.10 (mt, 4H:27+5β2)7
．． Go to 157. ! i3 (lllt, 9H (includes one exchangeable line): 67' I-6δ+68+1H
of he N Ha 1- CJ24 NH! +1'
H4+ 1'I''s) 9, -12 (s rl-+ wide, 'IH (exchangeable)
;N1-(20)1N). Example 4 5δ-dimedylaminomethylene pristinamycin F
(1,84 (1>) and 7N solution of methylamine ('1.
A method similar to that described in Example 3 was followed except starting from "Flash-1 [17 cc] [Eluate: Chloroform/methanol (9B/
After concentrating fractions 16 and 17 to dryness at 30°C under reduced pressure (2,7 kPa), 5δ-methylaminomethyl nonpristinamycin 42- (0,9a ) was obtained in the form of a yellow powder which melts at about 180°C. NMR spectrum: 0,98 (dd, IH75β 3.01 (d, 3H niNHCLa >7.17~
7.42 (II+), 8H: 6γ + 66 + 6ε + 1'
Hs + 1' H4+ = CHNHCHs ) 9, 8
0 (mt, I H (exchangeable) = NLLcHs>. Example 5 5δ-dimethylaminomethylene pristinamycin 1,
4 (1,840) and decylamine (3°19) and by flash chromatography [eluent: chloroform/methanol (98/2 vol)]. After purification and concentration of fractions 6 and 7 to dryness at 30°C under reduced pressure (2°7 kPa), 5δ-decylaminomethylenepristinamycin 1,1 (1,3+1
) was obtained in the form of a beige powder that melts at about 120°C. NMR spectrum: 0, 8-1.0 (flit; 7 t1; 2 γ
+ 5 β 2 + - (CHI) t (] pls
) 1.10 to 1.45 (110: 21H: 1γ+3
β=+3γr +−Cue (CHt)a CHa
) 3, 10-3.45 (L hit: 7H: 4NCHj
+36t+4β1+-cl~l NHCHi (CHi
)s) 7, 20~7.50<+beat; 81-1: 6γ ten θ
δ16ε+1'tls+1"1"4 +-CHNH)
9,95 (1++1; 1 t-1 (exchangeable) knee CH-N ratio-) Example 6 56-dimethylaminomethylene pristinamycin IA
(1,84,o) and pyrrolidine (1,420>), followed by "flash" chromatography [eluent: chloroform/methanol (98/ After concentrating fractions 12 to 22 to dryness at 30°C under reduced pressure (2,7 kPa'), 5δ-
(Pyrrolidin-1-ylmethylene) pristinamycin 1.4 (0,8++) was obtained in the form of a yellow powder melting at about 260 °C. NMR spectrum: 0.9 (n+t; 4H: 27+5β1) 1.48
~2.08 (up: 8H: 2βe+23, 4~3
．． 79 (lJp; 6H: 3δt +56 to 45- Example 7 56-dimethylamine, nomethylene pristinamycin 1
, 4 < 1.84 g) and N-methylpropargylamine (1,4a) and followed a method similar to that described in Example 3, starting from 1.84 g of Ethyl/methanol (90
/10 volume)] and purified under reduced Jf (2.7 hPa
) to dryness at 30°C, 5δ-(N-methylpropargylamino)methylenepristipmycin IA (0,7o) melts at about 175°C in the form of a yellow powder. Obtained with. NMR spectrum; 0.72 (dd; 11-1:5β2)2, 32-2
．． 58 (mt+t; 2H: 5β10-030
-1-1> 3.05~3.37 (up; 8H knee NCH* 14-NCf (a+3γ2+4β1) 46- 7.06~7.54 (up; 8H:6γ+6δ+6ε
, -CH-N<+1'H4+1' H8) Example
8 5δ-dimethylaminomethylene pristinamycin IA
(1,8417) and aniline (0,360), but follow a method similar to that described in Example 3 and perform "flash" chromatography [eluent:
IiI was prepared using ethyl acetate] under reduced pressure (2,7 kPa
) at 30°C until fractions 4 to 10 are concentrated to dryness, then 5δ-phenylaminomethylenepristinamycin IA (1,6
g> was obtained. NMR spectrum: 0.95 (dd; ll-1:5β2)2.45 (
(1;1)-1:5βl)3.60 (d;11-1
:5εξ)5.05 (d;1)−1:5ε1)5,
20 (d; 11~(; 5α)7, 25 (
(1; 1 t-l: -NH-CbHs)7~
7.50 (up; 131": 6γ+6δ+6ε+
1'H4+1' f-1s+ NHC6H5-Cl
-1-NH-) 7, 75 (+ld; IN: 1' HG) Example 9 5δ-dimethylaminomethylene pristinamycin IA
(0,9Or+ > and N-methylaniline (0,22
! A method similar to that described in Example 3 was followed except starting from
After concentrating fractions 10 to 14 to dryness at 30°C under reduced pressure (2.7 kPa), 56-(N-methylph]-nylamino)methylenepristinamycin 1 ,4 (0,40) is about 17
It was obtained in the form of a yellow powder that melts at 0°C. NMR spectrum-0,90 (up: 4H: 5βt +2γ)2,
50 (d; IH:5βl)5, 15 (up
; 2H: 4α+5α) 7, 10~7.40 (up
: 13H: 6716δ+6ε+1'H4+1'
8% +7, 75 (dd; 11-1: 1'H
b) Example 10 5δ-dimethylaminomethylene pristinamycin I
(1,84o) and 4-dimethylaminoaniline (1,
36111> and "flash" chromatography [eluent: chloroform/methanol (98/
After concentrating fractions 3 to 5 to dryness at 30°C under reduced pressure (2.7 kPa), 56-(
4-dimethylaminophenyl) aminomethylene pristinamycin TΔ (1 g) was obtained in the form of a brown powder melting at about 165°C. NMR spectrum: 0,90 (up; 4H: 2γ+5β2)2,4
0 (d; 11・1:5β1)4.55 (d;
11-1:Fiεt)5.05(d;IN:5ε
1) 5, 15 (tilt; 211: 4α+5α)7
．． 30 (knee below the unresolved peak-Nl-1-) 7.80 (dd: 1H: 1'HG) 50- Example 11 5δ-dimethylaminomethylene prisdinamycin 14
(2,77(1) and N-(2-hydroxyethyl)
A method similar to that described in Example 3 was followed except starting from propylene diamine (3,51>) and purified by "flash" chroma 1 to graphie [eluent: chloroform/methanol (85/15 vol)]. , fraction 19 at 30°C under reduced pressure T' (2,7 kPa).
After concentrating ~25 to dryness, 5δ-[3-(2-
Hydroxyethylamino)propyl]aminomethylenepristinamycin (0,9Fl) was obtained in the form of a yellow powder melting at about 162°C. NMR spectrum: 0.90 (1 day under 2γ: 5β2) 2.45 (d
:IH:5β1) 2.80 ([1); 2Hnee=-CI-1-NH-
C ratio) 3.15 ((Ip:4H: OH2NHC
Hi -) 3.5 (1 (rl wide + 1: 1 l-l: 5ε1)
3.75 (width: IH: CH20jzl) 5.1
5 (width 8:1+1:5α> 6.60 (up: I Ll Knee CHt -N H-
CH2−) 7,2C)−7,50(uparomatic pro1~n+=CJ
SatNH-) 7, 8f',) (drl; 1tl: 1' H
&>10.00 (width up: 1 H knee Cl-1-
NH-1) Example 12 5δ-dimedylnozminomethylenepristinamycin I
A (2,76 ft) and N-(3-amitubl]biru) G were prepared in the same manner as described in Example 3, except that the starting material was nolamine (4,86()). ) and purified by chromatography [eluent: 11 ['l form/methanol (85/15 volume)] at 30 °C under reduced pressure (2,7 kPa).
After concentrating the r-7 lactions 15-19 to dryness, 5δ-[3-N-bis(2-hydroxyethyl)aminopropylcoamino methylene pristinamycin 1,4
(0.95(1) was obtained in the form of a yellow powder which melted at about 164°C. NMR spectrum: 0.90 (2γ, under the IH triplet; 5β 2.5
0(d; 1H:5β1) Ratio ξ-) Ratio 2-) 3.45 (Width d; IH: 5εt) 3.65 (Width up; 4H: 2x 10H!0H) 4.90 (Width d; IH: 5ε1) 5.15. (Width dlH: 5α) 7.75 (dd; IH: 1' H! >10.2
5 (up; IH knee CH-N, L-) 53 Example 13 5δ-dimezalaminomethylene pristinamycin IA
(1,84(1) and 2-aminoethanethiol (1)
，! '1411J) and follow a method similar to that described in Example 3, except starting from ``Fludge''
] 71 ~ Purified by graphography [eluent: ethyl acetate/methanol (90/101)] and purified under reduced pressure F (2,7
After concentrating fractions 8 to 14 to dryness at 730 °C to
It was obtained in the form of a yellow powder that melts at 0°C. NMR spectrum: 0, 90 (up; 4H: 2γ+5β) 1,
45 (t: 11-1: -S ratio) 2, 45 (
d, IH: 5β1) 2, 70 (IIll: 2H: CHt S ) 3,
4 0 (up: 2H KneeNH-Cdanj >3,5
0 ((1; II-1:5εR54-4, 9.5 (dd: IH: 5εL)7.1
5-7.50 (01): 8H: 67+6δ+6ε
+1 'H4+ 1- Hs +-CH-NH>7.8
0 (dd; IH: 1' Hg) 10 (up;
I H: =CH-NH-) Example 14 5δ-dimethylaminomethylene bristino-phycin 1
,4 (2,76(] ) and ]N-phenylethylenediamine 4.0811> Example 3
and purified by "flash" chromatography [eluent: chloroform/methanol (98/2 vol) at 1 J: under reduced pressure (2,
After concentrating fractions 14 to 24 to dryness at 30°C and 7 kPa), 5δ-(2-phenylaminoethyl)aminomethylene pristinamycin 1,4 (1,
2(+) was obtained in the form of a yellow powder melting at about 172°C. NMR spectrum: 0.95 (2'r under methyl, If-1:5βl)2
．． 45 (d; 1t-1:5β engineering) 3.10-3.40 (IIp: 4H: CHE C ratio e
NhlC6H5) - 3゜45 ((i; 11-1:5ε2) 5.15 (width d: IH: 5α) 6.55~('), 80 (
++p; 4H near, 20-7.50 (11+1 aromatic proton not included +=C month-) 7,80 (dd; 1 Tol:1'Hi) 10,00
(up; 1 H: -CH-NH-) Example 15 5δ-dimethylaminomethylene pristinamycin IA
Example 3 except starting from (1,8'1(1) and 2-<2-aminoethyl)pyridine (2,44+7)
and purified by "Flash 1 1] 71 to Graphie [eluent: chloroborum/methanol (9515 volumes)]" and purified under reduced pressure (2
, 7 kPa) at 30°C until fractions 9 to 12 were concentrated to dryness.
-yl)]nitityl]aminomethylenepristinamycin 1,4 (1,2 g) was obtained in the form of a yellow powder melting at about 170°C. NMR spectrum: 0.90 (under 2γ[IH:5βt) 2.45
(d;11-(:5βl)3, 25 (till;
2H knee CH-, -Nl-1-) 3.45 (up: 3
H: 5εt included) 4.85 (up: 3H: 5ε
1) 5.10 (d; IH: 5α) 7, 10 to 7.45 (up; Aromatic proton containing 3H: 57- L 7, 75 (+1d; 1 t1:1'H6) 1 0,
OO (llp; III: N month knee 〇Ht) Example 16 5δ-dimethylaminomethylene pristinamycin r,
4 (1,84 (1>) and glycine (1,5!)) followed by "flash" chromatography [eluent: methylene chloride]. /methanol (80/20 container) 1, and fractions 9 to 16 were concentrated to dryness under reduced pressure (2°7 kPa) at 30°C, and then 5δ-
Carboxymethy58-ruaminomethylenepristinamycin IA (0°7(
]> was obtained in the form of an ocher powder which melts at a temperature of about 270°C. The infrared spectrum had the following absorption bands characteristic of pristinamycin: 3300 cm-1, 17450 IIl
-λ, 1600~1620cm", 1525cm-"
, 810 cm ”, 700 cm ” and also the group -CO
i- as the internal salt state): 1660-162
0 cm l and 1410 cm-10 Example 17 Sodium cyanoborohydride (0,43a) was converted into trifluoroic acid i! (1,2 cc) of 56-dimethylaminomethylene pristinamycin 1,4 (1211>) in tetrahydrofuran (230 cc); the resulting solution was stirred for 4 hours at a temperature around 20°C, then It was concentrated to dryness under reduced pressure (2,7 kPa) at 90° C. The resulting residue was purified by “flash” chromatography [eluent: chloroform/methanol (9515 vol)]; fractions 4-15 were Under reduced pressure (2,7
Concentrate to dryness at 30° C. at kF) a). This resulted in 5δ-methy1nonpristinamycin IA (5,5
0) was removed in a white crystalline state that melts at 2715°C. NMR spectrum: 0, 55 (dd; I I-I: 5β2) 2, 4
0 (+1; IH:5 β 1 )3.55 (d
d; 11~1:5ε2〉5.25(υD:2H:5α
+5εl)7.85 (dd; IH: 1' Hb
) 5δ-dimethylaminomethylene pristinamycin I
could be prepared as described in Example 1. Example 18 Trifluoro[1] acid (approximately 20 cc> was added over 15 minutes to a solution of 56-dimethylaminomethylene pristinamycin rA (19,50>) in isopropanol (570 cc) cooled to 5°C. Hydrogen Sodium boronate (0,4(1)) was subsequently added and the mixture was then stirred for 20 hours at a temperature of around 20°C.The reaction mixture was then heated under reduced pressure (2°7 kPa).
The mixture was concentrated to dryness at 30° C.; the resulting residue was dissolved in methylene chloride (400 cc). The solution was washed with distilled water (2X200 CC), dried over sodium sulfate, filtered, and the filtrate was dried under reduced pressure <2.7 kPa.
) and concentrated to dryness at 30°C. The residue was purified by "flash" chromatography [eluent: methylene chloride/methanol (97/3 vol)]; under reduced pressure (2
By concentrating fractions 17 to 34 at 30°C and 230°C, 5δ-methy1nonpristinamycin I,Q (5,7σ) was obtained in the form of a yellow powder that melts at about 230°C. The crude product 61- is sufficiently pure for use in all steps. ) Example 19 1- as described in Example 17 for 5δ-methylene pristinamycin, but using C-5δ-dimethylaminomethylenevirginiamycin S (2a) and sodium cyanoboronate (74o) as starting materials. It was carried out in the same manner as the i method. “Fusesh” chromatography [
Eluate: Chloroform/methanol (9B/2 volume loss)] and reduced by 1. f:'F (2,7k
After concentrating Pa)kTr30'cr75') Simine 2-5 to dryness, 5δ-methylenevirginiamycin S (1o) was obtained in the form of a beige powder that melts at about 190 °C. NMR spectrum: 0.35 (dd; IH: 5β 2.45 (dd; IH: 5β1) 3, 55 (dd: 11-1 : 5ε2) 5.25
(dd; IH: 5ε□) 5.25 (+beat; ll-1:5α) 62- 5δ-dimethylaminomethylenevirginiamycin S@ could be prepared as described in Example 2. Example 20 5δ-dimethylaminomethylene pristinamycin IA
(10,6(1) was added to an aqueous 0, IN aqueous solution of hydrochloric acid <420 cc) with stirring.Then, the resulting solution was heated to 20°C.
The mixture was stirred at a moderate temperature for 3 hours. Next, a saturated aqueous solution of sodium bicarbonate (30 cc) was added dropwise to obtain a pH value of about 4. The precipitated product was filtered off and then washed with distilled water three times (total 30
CC) Washed. After drying under reduced pressure (2.7 kPa) at a humidity of about 20 DEG C., 5b-human oxymethylene pristinamycin 4 (9.5o) was obtained in the form of a beige powder. The product was of sufficient quality for use as is in subsequent steps. However, it was also possible to make the glaze using the following method: Dissolve the crude 515-hydroxymethylene pristinamycin rA (9,50) in acid-resistant ethyl (50 cc) and pour the resulting solution into a 2.8 C1lI diameter It was poured onto a column of silica gel (100 fl.).Elution was first carried out with 1 tyl acetate (400 cc); the corresponding solution was discarded. Ethyl acetate (1600 cc) T"
Continuing the extraction #J: Reduce the pressure of the molten metal to F (2,7k
The mixture was concentrated to dryness at 30°C. This allows 5δ-hydroxymethylenepristinamycin IA
(6,30> was produced in a white crystalline state melting at 220°C. NMR spectrum: 0,69 (dd: I H: 5β 2.43 ((
1;111:5βl) 3, 40 (d: ll-1: !”)εl) 4.0
~4,2 (fli); 3to1:4α+5εl15
α) 8, 15 (s: 11-1: =CH-0H)
11.63 (S width; I H: =CH-0H) Example 21 Preparation of acetyl chloride at a temperature of about -20°C from 1 to 56 in methylene chloride (20CC) containing ethylamine (0,20) -Hydroxymethylenepristinamycin I, ((
1,8(1) and then the temperature was increased to about 20°C. The reaction mixture was subsequently stirred at this temperature for 20 hours,
It was then concentrated to dryness under reduced pressure (2,7 kPa) at 30° C.; the resulting residue was purified by “flash” chromatography with eluent: ethyl acetate]. Under reduced pressure (2
After concentrating fractions 4 to 7 to dryness at 30°C under 56-acetoxymethylenepristinamycin T,4 (0,7(] ) at 30°C, 56-acedoxymethylenepristinamycin T,4 (0,7(] ) is a yellow powder that melts at about 160°C. NMR spectrum: 0.60 (dd: IH: 5β,) 65-2, 25 (s; N-1: -COCH3>2
, 45 (d; 'I H: 5β1)3,
4 5 (fld; 11-1: bε!)5,
25 (rid: 1 t(: 5 α)5, 45
(d: 1H:5ε1)7.10~-1, 45
0 hit: 8H: 6γ+6δ166-+1' +14 +
1' 1-1s +=CH-0)7, 8 5 (d(
1;
A (1,8V) Rt, U. Soethyl chlorophosphate (tl, 34S/l to 1 (eye/)j outside 1f
According to the force θ similar to that described in K Kume m1ll 1ylJ 2 'l, the I-flash-1 talomad graph f-[, 16 appearance: Enal butyrate/methanol (!10/I C+ ≠i゛1it): Temporarily, 5δ-jetoxyphos was heated to dryness 14) by drying Fushictions 5 to 14 at 30'Q at 2.7 kl'a+ under +14 by J. Small sulfuroxymenarenzo'rinupupmycin 1.4 (11,8r) is produced in powdered form at about 6.t to -4 at about 150°C:
) I1. NMR spectrum: (1,55(dd + 1 // : 5β,)l) (t d I 67) : -Non 0 (0-C'
lit −(, JIJ2, 40 (d; l //
: 5β1) 3-40 (ad + l /7 : 5
a s )425 (d d d, 4H: -P
O(0-CH2-C1f,),)5.25 (d;
llf: 5α) 5.40 (d; iH: 5g,) 7, 10-7.55 (u7); 8〃:61+6a+6m
+ =C, 1l-0-+ 1'li, +1'E
, )7.85 (dd i 1lIx0.85:
1'1), lη4-isomer) f3(ddn111×0.
1 fi: 1'H6 wound] (sex form) Example 23 A solution of 56-hydroxymethylene purinutinamycin IA (2,'l) in methylene chloride (3ocr, )
At a temperature of about 0°C, 1 lyutylamine (0°42CC) and the next vcp-toluenesulfonyl chloride (o, 57
r) was added and the temperature was placed at approximately 20°G. The reaction mixture was stirred for 2 hours using a sieve.
Next, dry under reduced pressure (2,'lkPα) at 30°G; [flash] the attached residue.
The tuna was prepared by chromatography [extract: methylene chloride/methanol (9fi/4 volume 1)]. −λζ pressure (
2,7ir, P(L) l//: Frazi-' at 30℃
/ B Shrunk by 41 when dried to 4-6' / This 1/
d, 5δ-(4-methylphenyl)sulfogol" ximethylene pristinama, ion IA (:z, 2r) is a white powder with a haze of about 265 'r;
) 11. N MR spectrum: 0.450 (dd;Lll: 5β2)3.30
(ddH177:5g2) 5.25(d;l//:5α) 5.30 (ddIltf: 5g,)7,:(5-7
,90(,47Ji+13pH8H:4δ10-69-H7,85(dd ILH: t'B,)Example 24 The flow of chlorine gas was continuously added to methylene chloride (25cc) until a greenish-yellow color i14 was obtained. ) in a bath solution of phosphorous triphenyl (1,3 tfl) while maintaining the temperature between -20°C and -15°C. Phenyl (6 drops) was added followed by 5δ-human-ximethylene pristinamycin IA (4,1r), while the temperature was further maintained between -20°C and -15°C. The resulting solution was stirred at -15°C for 1 hour, then diluted with methine chloride/(25
4 cc of pyridine (CC) + acid solution was added dropwise. The reaction mixture was subsequently stirred for 30 minutes at a temperature of about 20°C, and then salt-formed @ (d = 1.19) ( 0.46 h) and methylene (50 mark) were added. The mixture was washed 4 times with distilled water (total of 100 fli);
Dry over magnesium and filter, then filter at 30°C under pressure (2, TkPa, ) at 71'.
Concentrate on a hill to dryness. [Flash-1 chromatography] [Flash-1 chromatography]
Prepare ThI with ethyl; and harden fractions 7 to 9 at 30°C under reduced pressure (2.7 kPa, l).
Peta drum, 5δ-chloromethylene pristinamycin I
A (1.2fl is about 190℃ 'M I#J!, "i-
It was obtained in the form of a beige powder. NMR spectrum: 0.55 (dd HIH: 5βt) 2.45 (d
;LM:5β1) 3.45 (tid;lH:5εsu) 5.3 0 (d; 1)l: 5α)545
(dN 111: 5βt)7.1b-7,60(
upI81J:61+6δ+6ε+1 /n4+11t
rW+=ctj-ct)7.85 (ddH111:
t'#61 Application Example 1 2-tmethylamine ethylamine (5,3r) at 25°C
? 5δ-dimethylaminomethyl in vinegar Iff (60ω) so as not to exceed r-
, 5)) was added dropwise to the liquid resistant solution. The obtained fC was stirred for 20 hours at a temperature of 20°C and 6°C, and then slowly poured into bicarbonate of water.
The evaporated mixture was diluted twice with dichloromethane (total 750 m
) Extract 762. The organic phases were combined, dried over magisium sulfate, filtered, and the filtrate was dried under reduced pressure <2. '1k
OA condensation was carried out at 30° C. until dryness. 'A7 ``Flash-1 Noromadography [Gushing liquid;
Noroform/methanol (90/10 volume box)]; Fractions 10 to 12 were purified under reduced pressure (2.7 kP (L)
The mixture was concentrated to dryness at 30°C. In addition to this, 5δ−
1.4 (3 t) of (2-dimethylaminoethyl)aminomethylene pristinamycin was produced in the form of a beige powder which bath melted at about 180°C. NMR spectrum: 0.90 (mtH4M:2r+5βl)Z 25 (
m t 16 R: -A' ((?Hal*)2,5
0 (mt i 311 : -CH2N' +5β,
)\3,25 (m t ; 2 H: -N-CH4-)
3.50 (mt i 2H: 5 #, +36.)
490 (mt! IH; 5 ml) 9.90
<mt; xH (replaceable with D, 0) knee N11-)
From the following ingredients, 5δ-(2-dimethylaminoethyl 73
- aminomethylene pristinamycin IA (product A)
G) was obtained: Produced AG O,lf Distilled water Sufficient amount to make 10 cc Application Example 2 5δ-dimethyl°aminomethylene pristinamycin I
AC1.84? ) and 2-diethylaminoethylamine (28Qu), and following the method described in Example 1 and the method of interpolation, and starting from [Flash 0,1
Chromatography [Eluate: Chloroform/methanol (9e/4 volume: prepared from lK, <2.7k under reduced pressure)
After concentrating fractions 9 to 131c to dryness at 30°C at Pα), 5δ-(2-soninal aminoethyl) aminomethylene pristinamycin IA (it) is a yellow powder that melts at about 150°C. Obtained with a similar source. IV MR Spectrum Near 4- 0.9 (normal t; 4B: 2γ+5β,) 1.1 (rn t H6H: -N (C11, -C
IlIl), ) 2.45 (dllH: 5β1) 3.50 (ηit + 2B: 5 at + 3δl
) 4.90 (unHIE: 5g,) 9.9 (ups 17 (replaceable): -CE-
From the Nll-1 order component, 5δ-(2-
A 5 ml solution of diethylamine ethyl) aminomethylene pristinamycin J (product AH) was obtained; product AM O, 11 0, 1N hydrochloric acid 1011° distilled water Sufficient amount applied to make 2 ml Example 3 5δ-tumethylaminomethylene pristinamycin IA
<2.76 N and N-methylene diamine (
2,221i'), and then by "flash" chromatography [eluent: chloroform/methanol (9515 vol)]. broken and under reduced pressure (λ
After concentrating fractions 16 to 20 to dryness at 30°C with
) was obtained in the form of a yellow powder that was resistant to melting at 174°G. A' M I (spectrum: 0.90 (1Lp14B:5β,) Z50 (upIIH:5β1) 2.7- I6 (up I4B: -NH-(CH2
), NH-)30 (below the unresolved peak, s 1
a Hnee NIICH,) 7.15-7.40 (upIIH: -CHNH-)
9.90 (up; IH: -CH-NHCH8
) From the following ingredients, 5δ-(2-methylaminoethyl)aminomethylene pristinamycin IA in the form of hydrochloride (
A 1% aqueous solution of the product AI) was obtained: Sufficient amount to make the product o, oar O1IN hydrochloric acid 031 in distilled water 3CH Application Example 4 5δ-tumethylaminomethylene pristinamycin I,
4 (1,84f) and 3-dimethylaminopropylamine (15 cc)) and followed a method similar to that described in Application Example 1, starting from "flash" chromatography [eluent: chloroform/methanol (
e o/lO volume t): 1 and then under reduced pressure (2,'
After concentrating fractions 12 to 15 to dryness at 80°C (lkPα) at 80°C, 5δ-(3-tumethylaminopropyl)aminomethylenepristinamycin IA (0,7f) was added in a ladle at 15°C.
It was obtained in the form of a yellow powder which melted at . NMR spectrum: 0.80-1.05 (mt H2N:27+5β,)
1,80 (m t i 2 II: -CH3CN
, -CH,-)2,. 35 (# l6HX O, 85
: -N (CH,)2th isomer) 2・40 (8, wealth e#x o, t 5: -N (
CM, ), second isomer) 240-2.60 (mt +3#: 5β, +
-CH2-N, )3,30 (tn, t I2H
: -NH-CE2- )3.50 (mt H2E
: 3δ, +5g,)4,. 90 (mt HtH:
5 m, )9.65 (up HtHxO,z s
: -CH-N11-second isomer) 9.90 (up: IHXo, 85 : -CH-N
E-1 78 -th isomer) From the following components: 5δ-(3-dimethylaminopropyl)amino7methylene/pristinamycin IA in the salt form (6.6% of the product AJ) #Liquid was obtained: Product AI O,11 0,2N salt 0.51 ff. Steamed water Sufficient amount to make 1.5 CC Application Example 5 5s-dimethylamine methylene pristinamycin IA
A method similar to that described in Application Example 1 was followed except starting from (2,76&> and l-dimethylaminoproboxylamine (3,06F) and "flash" chromatography (61At: chloroform / methanol (99/l volume)] and purified at 30°C under reduced pressure (<2.1 kPa) at 30°C.
Concentrate 22 to dryness

[7] After that, 5δ-(3-dimethylaminoprobox-2-yl)aminemethylenepristinamycin I,4(1,Or) was swallowed as a yellow powder that melts at about 160°C. N M'R spectrum: 1.05 (d $ 3H: -C1l-C1i3)
- 2, 30 (fl 16 1): -CB, -At
(CHs)t)145(d(1)I: 5 β, )
Z 80 ("pHI H: 7CIICHs) - 3.30 (under unresolved peak: -NH-CH,-
)3.45 (ILp12H: 5g, +36.)4.
90 (wpILII:5砿,) 7.1fi-7,40<ILl)i 1M:=CIIN
H-)9.110 (up; iH: -C”1l
-NH-) From the following components, 5δ-(3-
A 1% crystalline solution of dimethylaminoprob-2-yl) aminomethylene pristinamycin/l, 4 (product AK) was obtained: Product Arc 20~ ++, @, I A' Hydrochloric acid 0.2 CC distilled water 2c
Application Example 6 5δ-dimethylamine methylene pristinamycin l7 in sufficient amount to make c.
(2,76F) and 2-dimethylaminopropylamine (1,53v), and followed a method similar to that described in Application Example 1, and by "flash" chromatography [eluent: chloroform/methanol rs5/a volume i)) and purified under reduced pressure (2,'lk
Pα) at 30°C to concentrate fractions 10 to 14 to dryness, 5δ-(2-nomethylacinoglovir) aminomethylene zolistinamycin/IA (0,85 r
1 is obtained in the form of a deep-red powder that melts at about 175°C.
l - ta. A' Ai R spectrum: 0.90 (uLpB4//:2y+5β,)1.05
(d B 3H: CH-CH,)/ - 2,30 (# 6 H: -C”E (CHI)N(C
Hs) t) 2.45 (dil/7:5β1) 2 to 80 (ILl); 111: -C, 11C
H,) a, aO (under unresolved peak, 2 H: −
NH-C゛genus-) 3.45 (vP g 2H: 58g
+36. )4.90 (upIlH: 5g,) 7.15-7.40 (upHIH: -CBNH-
)9, 90 (up l I If : -C1l-
NE-) From the following ingredients, 56- (2
t0% aqueous solution of amine methylene pristinamycin J (product AL) was obtained. Diproduct AZ, 0.03 f -82- o, 1N hydrochloric acid 0.3 L C8 Application Example 7 5δ-dimethylamine/methylenepristinamy'/71
．． 4 (1,84&) and 2-amino-5-diethylaminopentane (a,16r), and followed a method similar to that described in Application Example 1 and used "flash"chromatography.; Chloroform/methanol (90/10 volume)] and fractions 15-27 at 30°C under reduced pressure (CLTkPα).
5δ-(b-diethylaminebent-2-yl)aminomethylene pristinamycin IA (o9y) was obtained in the form of a beige powder that melts at about 160°C. NMR spectrum: 1.00 (ddHIH:5β2) 1-25 ('rn t I6 H', -N(CH*
CHJx)2,. 45 (d; lH: 5β1)3
．． 45(dd I1)/:5g,)7.30(under aromatic groton: =CH-NH-17,85(dd
(IH: l'116) 10 (1Lp width 11 M:
-Nli-C1l-) 1 From the following ingredients, a polyhydric solution of 5δ-(5-diethylaminopent-2-yl)amine methylene pristinamycin 1,1 (product AM) in the form of saline is obtained. Obtained: Product AM 0.02 fl O, 1# Hydrochloric acid 0.2 Cr'. Distilled water 2 (sufficient amount to make υ) Application Example 8
Application Example 1 except starting from (1,84r) and N-
Following a method similar to that described above, the sheaths were prepared by ``flash'' chromatography (eluent: chloroform/methanol (98/2 volume)) and sheathed under reduced pressure (2
Fractions 15-24 were linearized to dryness at 30°C at 5δ-(2-pyrrolisonoethyl)amine methylene pristinamycin 7.4 (0,9
5f) was obtained in the form of a yellow powder melting at 183°C. NMR spectrum: 0.90 Cmt H4H: 2γ+5β, )3.45
(upg4H knee NH=CB, -+5g, +31.
) 4.9 0 (up l IB: 5 81)
-85- 7,2-7,4(tc p: /7?'-1-1"/
4 +L'llB +=Cl1-) 9,90 (m t II H: =(,'HNHOH
2-) A 1% solution of 5δ-(2-pyrrolidinoethyl)aminomethylene pristinamycin in vinegar was prepared from the following mixture: Product/IN Q, 02io, t IV salt dazzling 0.2 steamed water Did you apply enough force to make it 2cc? ll
9 5δ-nomethylabanomethelene pristinamycin l,
4 (2,76F) and N-(3-aminopropyl)
A method similar to that described in General Example 1 was followed, except starting from pyrrolidine (1,92f), and "flash" chromatography [eluent: chloroform/
Sheathed with methanol (9515 Tani Consultation) and pressure 7 (
2-'IkPα) at 30°C to dry to -86- fraction 10 ~ ] 5.
, 5J-(3-pyrrolisonopropyl) aminomethylenepristinamycin IA (1,,25r) at 170°C
It was obtained in the form of a yellow powder that melts at . NMR spectrum: 0.95 (up i IH: 5β2)2,45 (
d + l] broad IIH: 5β formula) 2.80 (under unresolved peak, 6H: 3, 30 (mt H2E':
-NH-CHv-)3.50 (tnt I2H:
3δ1+5gt) 4.90 (uF; IH:5a+) 7.15-7.40 (upHLH:=CμNH->0
, 90 (nZt; 1 // : =C'H-Nl
i-) From t, i'4 *, 1, 5δ-(3-pyrrolisonopropyl)aminothire/gurisutinamine 7in 1
, 1 (raw 1M Narui O) of 1 t water #4 elm was obtained: t,
I=, Iy'i,'thing An O,03? distilled water 3
Example 10 for C(1°:l@) 5δ-dimethylaminomethylene pristinamycin I,
Application Example 1 but starting from 7(2,765') and N-(2-amineethyl)piperidino(a,55r)
A method similar to that described above was followed and chromatography was carried out by "flash" chromatography [eluate: chloroform/methanol (9 o/x volume)] at 30 °C under LE (2,7 kPa). and fractions 13 to 17
5δ-(2-piperidinoethyl)aminomethylene pristinamycin I, 4(1,
5 fl were obtained in the form of a yellow powder melting at about 162°C. NMR spectrum: 0.90 <%pI4M:2f+5βt)2.7-3.
5 (up under the unresolved peak 12H NH-CH
t-) 3.45 (mt; 2H: 3δ, +5g,) 4.9
0 (m, t IIH: 5 #, 17.15-7.
40 (up HIH: -CBNH-)9,90 (
m t ; I H: -CH-NH-) From the following components, 5°δ-(2-bi017,/noethyl)aminomethylenepristinamycin I in the form of hydrochloride, (x of (product AP> % water liquor was obtained: product AP O, Og
f -89-o,t#堝[o,2cc Distilled water Sufficient potency application example 11 to make 2a- 8'-(2-amineethyl)7ulfoline (2,6r) and 0,5δ-simethyl Amine methylene pristarnamai'
/71 (], 84f) Applicable except for departing from ha9
ii t 1i (-Following a method similar to that described, and then using [flash] chromatography [injection fluid: chloroform/methanol (9515 each)] in a cell, reducing ”<2.Tkpα) at 30°C until the fraction 2l-aO is rotated, then bδ
-(2-mol)aminemethylene-7'+)
Stiff V: /I, 4 (0,8f) is about 172
It was obtained in the form of a beige powder at 20°C. N114R spectrum: 0.95 (uplIH:5β,) 3,30 (up H2#; -) JH-CH, -
)3.50 (upI2M:581 +3δI)4.9
0 (up; lH:5g,) 7.2-7.4 (up; lif:=CH-)9,
9 0 (m t HI H2 = C'M-NH-CB
,-) 5δ-(2-morpholinoethyl)aminomethylenepristinamycin I in the form of hydrochloride from the following components:
A 1% water bath solution of (Product AQ) was obtained: Product AQ, 4Q
0.02f O,I N salt rR□, 2 CC Distilled water Sufficient amount to make 2 marks Application Example 12 5δ-dimethylaminomethylene pristinamycin I
(276v) and 2-aminomethyl-1-ethylpyrrolidine (a, 66F)) according to a method similar to that described in Example 1 and by "flash" chromatography [ t1 effluent: chloroform/
methanol (419/1 valley 1 juice)] and fraction 10~ at 30°G under reduced pressure (2,7 kPa).
The starched dust obtained in step 1, 5δ-(l-ethylpyrrolidin-2-yl)methylaminomethylene pristinamycin/(1,3V), is melted in a beige powder at about 160°C. Attended. NAfB spectrum; 1, 10 (t; 311: -C'JI, -CH
,)! 1.95 (up 11H: -CH-HE-)Z8-
3.6 (tL7+; 411: -Cμ, N,
10-C1l, NH-)7.15-7.40 (1LpI
IH: -CHNH-) 1 of 5δ-(1-ethylpyrrolidin-2-yl)methylaminomethylenepristinamycin IA (product AR) in the hydrochloride form from the following components:
A polyhydric solution was obtained: Product AR 0.02f O1IN Hydrochloric acid 0.2ω Distilled water Sufficient amount to make 2 mApplication Example 13 5δ-dimethylaminomethylene pristinamycin 7.
4 (2,88F) and 3-amino-1-methylpiperidine (3,4t), and followed a method similar to that described in Example 1, and by "flash" chromatography [elution Liquid: Chloroform/methanol (95/s volume fit) Purified by IK and purified under reduced pressure (
After concentrating fractions 7 to 16 to dryness at 30°C with
(0,8f) was obtained in the form of a beige powder at -93-177°C. NMR spectrum: 0.90 (ηttH4/l:2γ+5β2) 1.5-2
．． 10 (mt I'III: 2β1 + 2β2 10
．． 45 (dIlll:5β1) a, 20 (mt i 7 H: -NCIIs 4
- in position 94- 7.15-7.40 (up; lfl:=CHNfl
-) 7.80 (?fit i xR: t'Bat9,
90 (mt; III: =CE-Nil-)
11.60 (g width IIH 2011) From the next IJy, 1 + 56- (1-
A 1% aqueous solution of methylpiperidin-3-yl) amizmetele/pristinamycin 7A (raw I2y: QsAS) was obtained: Product AS O,02t' 0,1 N Hydrochloric acid 0.2 mark distilled water 2 tsp. Enough lid 3-7 minnow 1-methyl piperidine/glue, M. WERBEL, A, CURRY, E, F, ELSLAG
ERhc, Noiess, J, Heterocyol
ic Cheml O1363 (1973). Application example 14 5δ-somethylaminomethylene glistinamycin I,
4(13,sr) and 4-amino-1-methylpiperidine (3,4t), followed by a method similar to that described in Application Example 1, and then a "flash" chromatography c i output. Solution: Chloroform/methanol (92.5/7.5 volume)] and purified under reduced pressure.
2. 'lkPα) at 30°C in fractions 15-20.
bales concentrated to dryness, 5δ-(1-methylpiperidin-4-yl)aminomethelene pristinamycin 71
．． 4 (4, Of) was obtained in the form of a yellow powder that was resistant to melting at 208°C. NMR spectrum: 0.40 (% pH4/7:2γ+2β2)235 (8
I3H: 1N-CHs)145(dIH:5
β1) −,3,20(llH under unresolved peak: 3.50(
dllH: 5g, ) 4.85 (IIH under unresolved peak; 5#l) 6
．． 65 Cd HIH: CIINH-)9.70(d
ddIHxo, l5: -CH-NH-first isomer) 10.08 <dd HIHXo, 85: difficult CH-N
il - second isomer) From the following components, 56- (1-cu 9
A 10 ml solution of aminomethylene pristinamycin IA (product AT) was obtained: Product A 7'0. t) 3 t O, lNmr* 0.3CC Distilled water () Sufficient force to make the s mark 4-amino-1-methylpiperidine is E, F. ELSLAGER, L, M, 1F'ERBEL, A, C
URRY. N, EEADEIV AND/, l0INSON, J, M
ed. It could be prepared by the method described in Chem, 17.99 (1974) K. Example for shoulder use 5 5δ-trimethylaminomethylenevirginiamycin, S
(0,8F) and 4-amino-1-methylpiperidine (
1,02r) and by "flash" chromatography [eluent: Co. 98-roloform/methanol (90/10 volume)]. J)
MH and under reduced pressure <2. After concentrating fractions 3 to 7 to dryness at 30°C at 'tkpa>, 5δ-(l-
methylbiveridin-4-yl)aminomethyl/bilsoniamycin S (o,ar) was obtained in the form of a beige powder which melted at about x95°C. NMR spectrum: 0.9 (upI4H:2γ+5β2)3.55 (d
dllll: 5m, )4.90 (up l lH:
5 #, )7.1θ~7.40 (1LF+aromatic proton+=CH-Ni1-) 7.70 (d d 1 lH: 1'H,) 10.1
<up Illl: =C'noI-NH-) From the following, 5δ-(1-methylbiperidin-4-yl)aminomethylenebilsoniamycin S(
A 5% aqueous solution of product A11) was obtained: Product AU 0.1t O,IN Hydrochloric acid 1.05% distilled water Example 16 5d-Dimethylaminomethylene Pristina Mai'/71
．． 4 (2,7617') and t-(2-7minoethyl)-4-methylbiperazine (2,151F) were used in a similar manner to that described in Example 1 for field 1, except that “Flash” chromatography [h
4 Effluent: Chloroform/methanol (95/!i volume)
] under reduced pressure (2.7 kpa, l at 30°C
After concentrating fractions 10 to 16 to dryness,
5δ-[2-(4-methylbiperazin-1-yl)ethyl]aminomethylene pristinamine 1,4Co,e
t) was obtained in the form of a yellow powder which melts at 15°C. NMR spectrum: 1.00 (upjlH:5β,) 2,30 (8I3H: /N-CE5)Z50
(up i 9/7: -C1l, -piperazine+6β,
) 2.90 (below the unresolved peak; - C bird - CE, -
N,) 3.30 (1-Le 'I) I 2E 2 -N
H-CH,-)3.50 (up(2H: 5g,-1
161) 4-90 (" pII H: 5 a I)
7.15-7.40 (ipIIM:=CHIVH-)
9.90 (upNIH: Tomi CM-HE-1) From the following ingredients, 56-[2-(4-methylbiperazin-1-yl)ethylcoaminomethylene pristinamycin IA in the form of a dense salt (product 101- A 10% aqueous solution of AV) was prepared: product AV
15m9 0.1A'ffi[0,15CC N-methylbiperazine (9,75r) was added to a solution of 2-bromoethylamine bromide (to, or) in absolute ethanol (60 (8l). 20% of the solution
Stirring was carried out for 16 hours at a temperature of °C' Pi degrees, and then the ethanol was removed at 30 °C under reduced pressure (<2.1 kPa). The oily residue was removed with chloroform (500C);
C). The aqueous phase was extracted with chloroform three times (150Ω in total). , the cornucopia phases were combined, dried over sodium sulfate, filtered, and the filtrate was dried under reduced pressure <2-
The mixture was concentrated to dryness at 30° C. (TkPct). The residue was distilled under reduced pressure (2,7 kP (Ll);
-(2-amineethyl)-4-methylbiperazine (4,
5f) -102- was produced as a yellow oil [Napoint (2,7kl'a) -1
18-b \ Application Example 17 5δ-dimethylaminomethylene pristinamy 771k
A method similar to that described in Application Example 1 was followed except starting from (4,0 g and e, x, pmi/(0,55 p) and "flash" chromatography [
Eluent: Chloroform/methanol (9515 volumes)]
After concentrating fractions 25 to 5o to dryness at 30°C under reduced pressure (27kpα), 5δ-
[2-(Imidazol-4-yl)ethylcoaminomethylenepristinamycin IA (204 g) was obtained in the form of a yellow powder that melts at 138°C. NMR subek)・ru: 0.90 (wpH4H:2γ+5β,)2.40 (d
broad HxH: 5β1) 290 (+117 below unresolved peak) HIH: 5 g,) 3.5
0 (d + 4H: 5 #, +3δ, -1--N
H-CH,-) 480 (under unresolved peak, 177
:5ε1)6,65 (up; 2 II',
II 1t':'NH histamine) 750 (IH at the 2-position of 81 histamine, 1f) 7.15 to 7
．． 40 hours (up HI II; =CHNH-)9.
65 (up i 1 //X O, 15 knee CH-N
H-second isomer) 9.95 (up1111×0.85
:=CE-HE-first isomer) From the following components, 5δ-[2-(imidazol-4-yl)ethylaminomethylene]pristinamycin IA in the form of hydrochloride (product, 4F
) was obtained: A sufficient amount of 2-dimethylamineethanethiol (2,t g) was added to acetic acid ( 40 cC) of 5δ-dimethylaminomethylene pristinamycin IA (1°84 I). The resulting solution was stirred for 105-20 hours at a temperature of around 20°C and then slowly poured into a saturated aqueous solution of IJium (bicarbonate); the resulting mixture was diluted with methylene chloride for 3 hours.
Extracted twice (400 cc in total). Combine the organic phases;
It was dried over magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure (2.1 kPa) at 30°C. The resulting residue was "flash" chromatographed (eluent: chloroform/methanol (96/4 vol)) with Tf 1 ML, + fractions 5 and 6 were combined and chromatographed at 30° C. under reduced pressure (2,7 kPa). It was concentrated to dryness. This allowed 5δ-(2-dimethylaminoether)thiomethylenepristinamycin IA (
0.81) was produced in the form of a yellow powder which melts at approximately 150°C. NMR spectrum: 0.68 (dd(IH:5βt) 2.32 (8i 6HX O,85: -CH,N(
C1l,), 1st isomer) 106-2.35 (8$ 6Hxo, 15 Knee CH direct(”Z
s) g second isomer) 2.45 (d ! IHx5βI
)2.65 (mt i 2H: -5C'H, -)
3.05 (t i 2H knee CH, Nri) 3.43 (
ddllJI: 5ε2) 5.15 (at unresolved peak: 5εI) 7.6
o(s width 11 If: =CH5-)7.83 (
mt l 17/: 1 'H6 two (D isomer) From the following components, one aqueous solution of 5δ-(2-dimethylamineethyl)thiomethylenepristinamycin IA (product, 4X) in the form of hydrochloride Obtained: Product AX 0.ll1 O1IN hydrochloric acid 1 cc Distilled water Sufficient amount to make 10 cc Application Example 1
9 5δ-dimethylaminomethylene pristinamycin IA
Application example 1 except starting from (3,681i) and 2-diethylaminoethanethiol (s, 511)
8 and purified by "flash" chromatography [eluent: chloroform/methanol (96/4 volume 1r)] and fractionated at 30 °C under reduced pressure (2-TkPa). 13-20
After concentrating to dryness, 5δ-(2-diethylaminoethyl)thiomethylenepristinamycin IA (
0,s 5 g) was obtained in the form of a beige powder melting at about 192°C. NMR spectrum: 0.65 (ddl17:5β,) 1, +js (t irises 6H knee N (CH, CH,),) 2
．． 42 (d irises IH: 5βl ) 2, 60 (q H4H knee N (CHICH,) t) 3
．． 42 (ddilH: 5g,) 510 (below unresolved peak, IH: 5ε,) 7,5
g (8Ill wide H111:=C亙-5-)7, 82
(dd H1//xO,95: 1'B6 first isomer) 7.98 (dd i 14X0.05: 1
'H6 second isomer) From the following components, 5δ in the hydrochloride state
-(2-Diethylamine ethyl)thiomethylene pristina: ytA, 1 ml aqueous solution of (product AY) was obtained: Product AY 0.04 I1 0, IN Hydrochloric acid 0.4 cc Distilled water 4 cc Application Example 20 5δ-dimethylaminomethylene pristinamycin IA
(3 g) and 3-dimethylaminopropanethiol (0
, 41) and "flash" chromatography [eluent: 109-chloroform/methanol (92,5/7.5 vol.)]
30' under reduced pressure (2,7k I)α)
After concentrating Horns 10 to 17 to dryness at
It was obtained in the form of a beige powder that melts at . NMR spectrum: 0.70 (ddglH25β, ) 1,90 (up; 2H25-C11,CH,
CH, Ngu) 2.20 (s; 6H knee N(ri,)
,) 2.40 (dHIH:5β,) 2,90 (up; 2H knee CH, -Ng) 3.
45 (ddllH:5all)7.65(g width 1
tH: =CH-5-) An aqueous solution of 5δ-(3-dimethylaminopropyl)thiomethylene pristina 110-mycin IA, (product AZ) in the form of hydrochloride was obtained from the following components: : Product AZ O,03f O1IN Hydrochloric Acid Q, 3 cc Distilled Water Sufficient amount to make 3 cc Application Example 21 5δ-dimethylaminomethylenevirginiamycin S (
1,811) and 3-dimethylaminopropa/thiol ((1,481)) and followed a method similar to that described in Application Example 18, and by "flash" chromatography [eluent; chloroform/ Tlfjllm with methanol (9515 volumes) and extract fractions 5 to 1 at 30 °C under reduced pressure (2,7 k Pα).
After concentrating 4 to dryness, 5δ-(3-dimethylaminopropyl)thiomethylenevirginiamycin, s(
o, rg) was obtained in the form of a beige powder melting at about 140°C. NMR spectrum: 0.50 (ddilff: 5βri2 (u p 2 H', -5CH3-C2b-CII
tNgu) 2, 35 (8i 6H: -5(C1l,)
sN(CH,), )260 (t i 2 H: −
5CH, -CM, CH, -N, )a (t l 2
n: -scg, cH, cm, y< )3.35 (
ddi, IH: 5εt) 4.90 (ddHIH: 5g,) 520 (ArtpilH: 5α) 7.60 (arl) wide: IH: =CIj-5-)
7.80 (dd: 177: 1'H,) From the following components, 5δ-(3-dimethylaminopropyl)thiomethylenevirginiamycin S in the form of hydrochloride (product A
A 10% aqueous solution of AA) was obtained: Product AAA O, II! 0.2N Hydrochloric acid 0.52ee Distilled water Sufficient amount to make 1 cc Application Example 2
2 5δ-dimethylaminomethine/pristinamycin IA
Application example 1 except starting from (4 g) and 3-dimethylamine-2-methylpropanethiol (0,71)
8 and purified by "flash" chromatography [eluent: chloroform/methanol (94/6 vol)] and purified under reduced pressure (2
, 7k Pα) at 30°C until dryness,
5δ-(3-dimethylamino-2-methylpropyl)thiomethylene pristinamycin 1A (0,96Ji')
was obtained in the form of a beige powder that melts at 234°C. NMR spectrum: 0.65 (ddBIH: 5β,) 113- 1.05 (d; 3H: -CHCH,) 2.25 (J; sH: -N(CH,), )2
．． 40 (dude IH: 5β1) 3.15 and 2.90 (ABX system, 2H: -cm
,y< )3.45 (d width 1277:5g) 7.75 (dd 1177xO,80: 1'H6
isomer) 7.95 (ddllHxo, 20:1'Z
/, second isomer) From the following components, 5δ- in the form of hydrochloride
An aqueous solution of (3-dimethylamino-2-methylpropyl)thiomethylenepristinamycin IA (product AAB) was obtained: Product AAB O,031! 0,IN Hydrochloric acid 0.38c Distilled water To make 3Ce, sufficient amount of 3-dimethylamino-2-methylpropanethyl was able to be prepared by the following method: Suhrium (0,026F) was anhydrous Added to a solution of N,N-dimethyl-3-acetyl-2-methylpropylamine (5.33 g) in methanol 114-(socc). The resulting mixture was heated under reflux for 7 hours, then the methanol was removed under reduced pressure (2.7 Pa) at 50°C. The residue was distilled under reduced pressure (2,7k Prx). Distillation was carried out at 2.7 kPα and 56°C, which produced 3-dimethylaminol 2-methylpropanethiol (0,91) as a yellow oil. N,N-dimethyl-3-acetylthio-2-methylpropylamine could be prepared in the following manner; thiol acetic acid (1s, 7cc) was mixed with isopropanol (t
2occ) of N,N-dimethyl-1-chloro-2-methylpropylamine (29,51). The resulting mixture was heated under reflux for 48 hours, then the isopropanol was removed under reduced pressure (2,7 kpa) at 60°C. The resulting residue was dissolved in a saturated aqueous solution of sodium bicarbonate (
100 cc) and the aqueous phase was extracted three times with ethyl ether (600 cc in total). The organic phases were combined, dried over magnesium sulfate, filtered, and the filtrate was concentrated to dryness. The resulting residue was purified by "flash" chromatography [eluent: chloroform/methanol (90/10 by volume)]; fractions 6 to
10 together and 30 under reduced pressure (27kpa)
Concentrate to dryness at °C. This produces red oily N.
, N-dimethyl-3-acetylthio-2-methylpropylamine (5,s 7g) was produced. N,N-dimethyl-1-chloro-2-methylpropylamine J, P. BOURQUIN et al., Eelv. Chim, Acta, ±1.1072 (1958)
It could be prepared by the method described in . Application example 23 5δ-dimethylaminomethylene pristinamycin +A
(4#) and 2-dimethylamine-2=methylpropanethiol (t, 14 g) according to a method similar to that described in Application Example 18, and then by "flash" chromatography. [Eluate: Chloroform/methanol V (92/8 volume)] Purify fraction 12 at 30'C under reduced pressure (2, TkPa).
After concentrating ~30 to dryness, 5δ-(2-dimethylamino-2-methylpropylene)thiomethylenepristinamycin I'A (1,4,9) melts at approximately 200 °C in beige color. NMR spectrum: 0.55 (ddIIZ/xO, 20,: 571@second isomer) 0.68 (dd rich 11/xO, 80: 5
β, first isomer) 1, 15 (a, 611: −
C(CH,:),-)2.30"i 6Hxo-80neeN<CHs)ttg
! 2nd isomer) 2.4o (dH111: 5β1) 280 (under unresolved peak:, 5-CB-) 3.4
2 (dd; IH: 5t,) 7.55 (8 width: IH:=CH-5) 7.80 (ddllHXo, 80
:1'776 first isomer) 7.98 (dd i IH
Xo, 20: 1'H, second isomer) From the following ingredients, 5δ-(2-dimethylamino-2-methylglobil)thiomethylenepristinamycin IA (
An aqueous solution of product AAC) was obtained: product AAC0.031 hydrochloric acid 0.3 ml! Distilled water Add enough 2-dimethylamino-2-methylpropanethiol to make 2 cups.
,R,5NYDER,J,M,5TEWART and J
, B., ZIEGLER, J., Am., Chgm., Soc.
,,6 9. -118-2672 (194?). Application example 24 5a-dimethylaminomethylene pristinamycin IA
Application Example 18 but starting from (4#) and 2-(pyrrolidin-1-yl)ethanethiol (1,1,9)
and purified by "flash" chromatography [eluent: chloroform/methanol (96/4 t)] under reduced pressure (2,
After concentrating fractions 9 to 15 to dryness in aooc at 7k Pα), 5δ-[2-(pyrrolidine-1
-yl)ethyl]thiomethylene pristinamycin IA
, (1,3,9) was obtained in the form of a beige powder that melts at about 1'800G. N Af / Ispec) Le: 0.65 (dd H111”, 5β1) 245 (
df IH: 5β1 ) and -5CH, -) 3.45 (dd i 177: 5't,) 7.60
(11 width (I B: = Cll-5-) 7.85 (
dd HxH: 1 'H6) 5δ-[2-(pyrrolidin-1-yl)ethylcothiomethylene pristinamycin IA (product AAD) in the form of hydrochloride from the following components:
A 1% aqueous solution of the product A A D o, was obtained. 3 g O,IN Hydrochloric acid 0.3- Distilled water Sufficient amount of 2-(pyrrolidin-1-yl)ethanethiol to make 3 ml J, W, IIAEF
FELE and R,Tr',BROGE,proc. Sci, Toilet Goods As5oc, 32
．． 52 (19, Fi 9 ) [C'hem, Abst
It could be prepared by the method described in J. R., 54, 17234 e (1960)). Application example 25 5a-dimethylaminomethylene pristinamycin rA
(4Ii) and 2-(t-methylpyrrolidin-2-yl)ethanethiol (1,74F), but following a method similar to that described in Application Example 18 and using "frateuil" chromatography [ Eluent: Chloroform/methanol (92/8 volume)], and fractions 12 to 22 were concentrated to dryness at 30°C under reduced pressure (2,'1 kPa), and then 5δ-[2-
(1-Methylpyrrolidin-2-yl)ethylkothiomethylenepristinamycin IA (1,33Ii)12
1- was obtained in the form of a beige powder melting at about 215°C. NMR spectrum; 0.65 (ddSIH:5βf) CB. 2.40 (d; iH: 5β,) 2.48 (8; 3H; > N-CH5 pyrrolidine) 3
．． 40 (dd B IH-5g,) 7.50 (8 wide i1H:=CH-) 7.80 (dd; lX0.85:1'J7s first isomer) 8.00 (dd mouth Hx O-15 : 1 'H6 second isomer) From the following components, 5δ-[2-
0.6 of (1-methylbilysin-2-yl)ethylcothiomethylene pristinamycin IA (product AAE)
An aqueous solution of 2-(2-acetylthioethyl)-1-methylpiperidine (157 #
) and sodium (except starting from 0,071
Application in the preparation of 3-dimethinotoamino-2-methylpropanethiol 2-(1-methylpyrrolidin-2-yl)ethanethiol could be prepared as pA by a method similar to that described in Example 22. This resulted in a red oily product (12.2#). 2-(2-chloroethyl)-1-methylpyrrolidine (
x2.7#) and thiol acetic acid (6,Bcc) for the preparation of 1A,U1,A',#-dimethyl-3-acetylthio-2-methylpropylamine as described in Application Example 22. Depending on the method, 2-(2
-acetylthioethyl)-1-methylpyrrolidine could be prepared. This produces a red oily product (xs
, 7Ii) was generated. Application example 26 5δ-dimethylaminomethylene pristinamycin IA
(ma op) and 4-mercapto-1-methylpiperidine (0,481), and following a method similar to that described in Application Example 18, and "Flash"
It was purified by chromatography [eluent: chloroform/methanol (9 o/lo volume)] and purified under reduced pressure (2,'
After concentrating fractions 15 to 19 to dryness at 30°C at lkPα), 5δ-(1-methylpiperidine-
4-yl)thiomethylenepristinamycin IA (1,
2 g) was obtained in the form of a yellow powder melting at about 170°C. NMR spectrum: 0,68 (dd H1, Z/: 5β,)2,3
0 (s I3 II : 7N-CH3)2.45(
dHlll:5βI) 3.05(ηtt; III: -5-CH-)
3.40 (5 g in ddlll,) 5.15 (d l111: 5 g,) 7.67 (#
Width i 1 H: =Cll-3-) 7.55 (dd richness 111x O, 85: 1 'H8 first isomer) 8.0
(dd 11Hx O[l 5 : 1 'E6 second isomer) From the following components, 5δ-(1-methylpiperidin-4-yl)thiomethylenepristinamycin IA (product AAF) in the form of hydrochloride An aqueous solution of 4-mercapto-1-methylpiperidine was obtained: product 0.05, F-125-0, IN hydrochloric acid Q, 5 eQ distilled water Sufficient amount of 4-mercapto-1-methylpiperidine to make 5 cc of HlBARRER and R,
E,LYLE,J,Org,Chem. 27.641 (1062). Application Example 27 5δ-dimethylaminomethylene pristinamycin IA
Application example 18 but starting from (411) and 1-ethyl-3-mercaptopiperidine (o, s l )
and purified by "flash" chromatography [eluent: chloroform/methanol (92/l'1 Jt)] and purified under reduced pressure (
2,7 k P ct ) at 30°C from fraction 6
After concentrating g to dryness, it melts at about 175°C.
δ-(1-ethylpiperidin-3-yl)thiomethylene pristinamycin 126-ene ■Δ(1,],!iJ) was obtained. #MR spectrum: 0, 7 (1 (s ra) wide, I II': 5β
, ) 1, 2 fl (t i 3 II : -C1l
, CM, ) 2.45 (d width i 1 II: 5β
1) 7.5O (8 width, 1 n: =cH-s-)
7.80 (dd H17/xO, 80: 1 'H6
(isomer) 7,9 b (dd, I II x
O,20: 1 '11 a second isomer) From the following components, 5δ-(1-ethylpiperidine-3
An aqueous solution of thiomethylene pristinamycin IA (product AAG) was obtained: product A,,4 GO,031! O,IN salt p 0.3 cc Distilled water Sufficient amount 1-ethyl-3 to make 3 cc
-Mercaptopiperidine kJiJ. E, BIEL et al., J, Am, Chgm, So6. 'l'
1, 2250 (1955). Application example 28 5δ-dimethylaminomethylene pristinamycin IA
(3,ON) and N-(2-mercaptoethyl)-N,
Ml, Ml-trimethylethylenediamine (0,551
A method similar to that described in application example 18 was followed except starting from 1) and "flash" chromatography [eluent: chloroform/methanol (90/
10 volume t) :] Purified from K and purified under reduced pressure (2,7k P
After concentrating fractions 17 to 24 to dryness at 30 °C at α), 5δ-[2-(2-dimethylamine ethyl)methylaminoethyl cothiomethylene pristinamycin t A (i, o II) It was obtained in the form of a yellow powder that melts at about 160°C. NAfR spectrum; 0.68 (ddllR: 5β, ) 2.30 (a B 311 : -NCIf, ) - 2,40 (<1117/ : 5β1) 24-3. t(
a month 8H knee S(Cμ,), N-(CH,), Nku)3
．． 40 (ddi 177:5ε,) 5, 10 (mouth H under unresolved peak; 56.) 7.5 B (s r
l] Wide SIH:=Cμm5-)7.80 (dd i
tJ7: 1'Ha) From the following components, 5δ-(2-
(2-dimethylaminoether) methylaminoether]thiomethylenepristinamycin 1 person (product AAII)
A 1% aqueous solution of was obtained: To make 3 cc of product AAHo, oay distilled water, sufficient amount of N-(2-mercaptoethyl)-N,N',N'-trimethylethylenediamine was prepared in the following manner. 129- Could be: Ethyl 2-mercaptoethyl carbonate (5,0 g) was heated under reflux in toluene (40 g).
cc) to a solution of N, Ml, Nl-)limethylethylenediamine (10,2, P). After 5 hours under reflux, toluene was added under reduced pressure (2,'1 kPa) for 5 hours.
It was removed at 0° C. and the residue was distilled at this pressure. 27
kPa, distilled at 105°C to form N-(2-mercaptoethyl)-N,N',Nl-trimethylethylenediamine in a yellow liquid state. Ethyl/L/2-mercaptoethyl carbonate beam, D
, REYNOLDS, D., L., FIELDS and I)
,L. JOHNSON, J, Org, Chem,, 26.51
25 (1961). Application example 29 5δ-dimethylaminomethylene pristinamycin sA
(4 g) and 1,3-bis(dimethylamino)propane-2-thiol (2Il) 130- Follow a method similar to that described in Application Example 18, except that [Eluate: Chloroform/methanol (92/Fl volume)]
After concentrating fractions 32 to 56 to dryness at 30°C under reduced pressure (27 kPa), 5δ-
[l,3-bis(dimethylamino)prob-2-yl]
Thiomethylenezuristinamycin IA (1,6,P) was obtained in the form of a beige powder that melts at about 190°C. NMR spectrum: 0.55 (dd di 111 x 0.80: 5β2 second isomer) 0,67 (d d i 111 x O,
20: 5β, first isomer) 2,30 (up I6
II: -, N(C5s), )28-3.2 (u
pJ 47/: -S(? II (CH2#1)
2) 7.62 (up H111: =C', H-5
−)? , 80 (dd HIHxO, 80: 1'H
6th - first body) 7.98 (dd) 1#xO, 20:1
'77, second isomer) From the following components, 5 in the form of hydrochloride
δ-[1,3-bis(dimethylamino)prob-2-yl]diomethylenepristinamycin IA (product AA
A first aqueous solution of I) was obtained: Product AAI 0.03 g 0. I N hydrochloric acid 0.3 cc Distilled water Sufficient amount 1,3-bis(dimethylamino)propane-2-thiol to make 3 cc J, M,
Stewart, J. Org. Chem. 29.1655 (196'4). Application example 30 5δ-dimethylaminomethylene pristinamycin ■A
(a, oII) and 1-(2-mercaptoethyl)-4
A method similar to that described in application example 18 was followed, except starting from -methylpiperazine (0.58p) and "flash" chromatography [eluent: chloroform/methanol (87.5/12.5 vol. leaf)〕
-C30 under reduced pressure (2,7 kPa)
After concentrating fractions 16 to 30 to dryness at
e g ) was obtained in the form of a beige powder melting at about 170°C. NMR spectrum: 0.56 (ddllHXo, 20:5β, first isomer) 0.68 (ddI17/xo, 80:5β, second isomer) 240 (a; 3If”, 1NcHs
)2.5-3(u71+12//knee S(C!!,)
, N (+ all -CIIl of piperazine) 3.42 (ddH11T'', 5g,) 512 (d wide; 581) 7.60 (8 wide 11 H: =CH5-) 133- 7.80 (c /dHIH: 1'H6, mixture of two isomers) 5δ-[2-(4
-Methylpiperazin-1-yl)ethylcothiomethylene pristinamycin! An aqueous solution of A (product AAJ) was obtained: Product AAJ 0.0511 0, IN Hydrochloric acid Q, 5 CO Distilled water Sufficient 1 l-(2-mercaptoethyl)-4 to make 5 cc -Methylbiheracin, D, R
EYNOLDS et al., J. Org. It could be prepared by the method described in Chgm, 26.5125 (1961). Application example 31 5δ-dimethylaminomethylene pristinamycin IA
(4,OF) and 1-(3-mercaptopropyl)-4
-A method similar to that described in Application Example 18 was followed, except starting from methylpiperazine (1,5,9), and "flash" chromatography -1-, [eluent: chloroform/methanol] (95
15 volumes 11)] and purified under reduced pressure (2.7 kpa)
After concentrating fractions 24 to 41 to dryness at 30°C, 5δ-(3-(4-methylpiperazine-1
-yl) propylcothiomethylene pristinamycin I
A (2,06iI) was obtained in the form of a beige powder melting at about 190°C. A', Ai H spectrum; 0.68 (dd H111'', 5β,) 1.90 (
information t i 2 II knee CH, -CMllCH, Ngu) a, 45 (1Lp view IH: 5ε2) 7.64 (8 width wide mouth 11 x 0.80: =CH-S-
1st isomer) r, ra (a width HIHxO, 20:=C
B-5-second isomer) 7.80 (dd H1/7xO
, 80: t'H6th isomer) 7.98 (ddlll
lco, 20:1'H6 second isomer) From the following components, 5δ-[3-(4-methylpiperazine-1
-yl) propylcothiomethylene pristinamycin I
A, 10% solution of (product AAK) was obtained: 5δ-[3-(4-methylbiheracin-1-yl)propylcothiomethylenepristinamycin IA (product A 10% solution of the product AAK) was obtained: Product AAK O, 05g 0. 3-dimethylamine- except starting from sufficient 1-(3-acetylthiopropyl)-4-methylpiperazine (iooy) and sodium (0,46F) to make 0.5 me Application for preparing 2-methylpropanethiol 1-(3-mercaptopropyl)-4-methylpiperazine could be prepared similarly to the method described in Example 22. 0.13 kP
a, distilled at 133°C to yield 1-(3-mercaptopropyl)-4-methylpiperazine (64,8F/) as a yellow oil. t-(3-chloropropyl)-4-methylpiperazine (1, a s 11 ) and thiol acetic acid (68,5 g
1-(3-acetylthiopropyl-4- Methylpiperazine could be prepared. It was distilled at 0.13kPaz'60°C and 1-(3-
acetylthiopropyl)-4-methylpiperazine (10
9,9) was produced as a yellow oil. Application Example 32 137- 5δ-dimethylaminomethylene pristinamycin Ip
- (4,0 g) and 3-mercapto-2-methylpropylammonium iodide (13 g), and followed a method similar to that described in Application Example 18, and by "flash" chromatography [eluent :chloroform/methanol (80/20 volume)], and fractions 12 to 22 were concentrated to dryness at 30'C under reduced pressure (2,7k pα), and then 5δ-(2
-Methyl-3-trimethylammoniopropyl)thiomethylenepristinamycin IA iodide (1,05Ji
T) was obtained in the form of an ocher powder which melts at about 150°C. NMR spectrum: 1.05-1.35 (u7)+8H:11+3rt13β138-290(γ+tI3.11:4β,-1--S-C
1l, -) 3.20 (mt +?//: 4NCH
B+4β1+3δ. ■ 3.40 (mt +911: -N(CM,),
) From the following components, 5δ-(2-methyl-
3-trimethylammoniopropyl)thiomethylene°
A polyhydric solution of listinamycin IA iodide (product AAL) was obtained; product AAL O,02,F O1N hydrochloric acid 0.2 cc distilled water 2 cc sufficient amount of 3-iodide Mercapto 2-methylpropylammonium could be prepared in the following way: sodium methylate (0,
024g) in methanol (iscc) was dissolved in 3-acetylthio-2-methylglobylammonium dinitride (3,s
It was added to the solution of I) at a temperature of about 20°C. The resulting mixture was heated under reflux for 1 hour and then left at ambient temperature for 16 hours. Methanol under reduced pressure (2,7k pα)
It was removed at 50°C. Improper tool (3S) removes the residue.
CC) for 1 hour, filtered the white suspension and then dried the material on the filter paper. This results in 3-merca 7”12-methylpropylammonium shoide (3,111)
was produced in the form of a beige powder which melts at 120°C. 3-Acetylthio-2-methylpropylammonium iodide could be prepared in the following manner: methyl iodide with N in acetonitrile (35 cc). After adding to a solution of N-dimethyl-3-acetylthio-2-methylpropylamine (3.5 g) and stirring at a temperature of about 120° C. for 18 hours, the precipitate was filtered off and then dried. This produced 3-acetylthio-2-methylpropylammonium shoide (3,sEl) in the form of a white powder that melted at 181'C. Application example 33 5δ-dimethylaminomethylene pristinamycin +A
(t, 5411) and the sodium salt of 2-mercaptoethanesulfonic acid (a, 2 s 11 ), but following a method similar to that described in Application Example 18 and using "flash" chromatography [elution Liquid: methylene chloride/methanol (911/10 volume dish)], and after concentrating fractions 6 to 14 to dryness at 30°C under reduced pressure (2,7k Pα), 5δ-
(2-Hydroxysulfonylethyl)thiomethylenepristinamycin+A(o,5II) was obtained in the form of a yellow powder that melts at temperatures above 280°C. The spectrum contains the characteristic absorption bands of pristinamycin: 1745.1680.1650, 141-1525.815.740 705 cm-1, 10 groups-5
0, H characteristic absorption band (1200 鑵-1 (wide) and 10
50cIL″″1]. From the following ingredients, 5δ-(2-hydroxysulfonylethyl)thiomethylenepristinamycin IA (product AA
A 5% aqueous solution of kf) was obtained: product AAM 0.1
1 Sufficient amount to make 2 cc of distilled water Application Example 34 5δ-(4-Methylphenyl)sulfonyloxymethylene pristinamycin I in methylene chloride (500c)
A solution of (5,277) was prepared as 1-(2-mercaptoglobil)-4-methylbi2 in ethanol (sOcc) with the addition of sodium ethylate (0,87Il).
gin (0.87N). The reaction mixture was stirred for 16 hours at a temperature around 20°C and then diluted with methylene chloride (500ω) and 142-distilled water (1o o cc). After stirring, the aqueous phase was extracted twice with methylene chloride (50 cc in total). The organic phases were combined, dried over magnesium sulfate, filtered and the filtrate was heated at 30°C under reduced pressure (2,1 kPct).
It was concentrated to dryness. The residue was subjected to "flash" chromatography [eluent: chloroform/methanol (9
7,5/25 volume)]. Fraction 33~
80 together and under reduced pressure (2,7k p a )
The mixture was concentrated to dryness at 30°C. As a result, 5δ−
[3-(4-methylpiperazin-1-yl)prop-2
-yl] thiomethyleneprisbu namycin IA (
1,25F) was obtained in the form of a beige powder melting at about 195°C. NMI? Spectrum: 0.70 (dd 117/: 5β,) 1.25 (
d; 3H: -C1l-CH,)2.30(8I3
B: N-CB, ) 3.4 g (dd; IH: 5 im) 7.55
(dd width i1H: 11H,) From the following ingredients, 5δ-[3-(4-methylbiperazin-1-yl)prop-2-yl]thiomethylenebristinamycin in the form of hydrochloride/
A 10% aqueous solution of IA (product AAN) was obtained: product AAN 0.0311 0, IN hydrochloric acid 0.3 cQ l-(2-mercaptopropyl)-4-methylbiperazine was prepared by propylene sulfide (19 cc) and N - Prepared by heating methyl verazine (429 cc) at 100°C for 16 hours. Distillation at 1.31c Pα, 105°C yielded a colorless oil (a2e). Application Example 35 Starting from 5δ-(4-methylphenyl)sulfonyloxymethylenepristinamycin IA (5,2F), 1-dimethylaminopropane-2-thiol (0,6 g) and sodium ethylate (034 g) follows a method similar to that described in Application Example 34, and
Purified by "flash" chromatography [eluent: chloroform/methanol (9515 vol)], fraction 16 was purified at 30°C under reduced pressure (2.7k pα).
After concentrating ~38 to dryness, 5δ-(3-dimethylaminoprobow-2-yl)thiomethylenepristinamycin+A (1 g) was obtained in the form of a yellow powder melting at 172°C. NMR spectrum: 0.65 (dd IH: 5β,) 2,30 (a 1611: -A'((1'H,)
, )145-7.60 (8 width B t H: =CH-8-)'1.
85 (dd7.'IB', 1'lf6) 5 t aqueous solution of 5δ-(3-dimethylaminoprobow-2-yl)thiomethylenepristinamycin IA (product AAO) in the form of hydrochloride from the following ingredients: was obtained: Sufficient 1-dimethylaminopropane-2-thiol to make the product AAO 0.03 fl O,IN Hydrochloric acid Q, 3 cc Distilled water 0.6 cc 5, D, TURK
et al., J. Org. Chgtn., 29, 974 (196
It could be prepared by the method described in 4). Application Example 36 5δ-(4-methylphenyl)sulfonyloxymethylene pristinamycin rA (6,s#), 5-diethylaminobencune-2-thiol 146- (1,05,9) and sodium ethylate (1 ,05
A method similar to that described in application example 34 was followed, except starting from I), and "flash" chromatography [eluent: chloroform/methanol (97,
5/2.5 volume)] and purified under reduced pressure (2.7k
After concentrating fractions 47 to 65 to dryness at 30°C in Pα), 5δ-(5-diethylaminopent-
2-yl)thiomethylenepristinamycin IA (
1, 3, 21! ) was obtained in the form of a beige powder which melts at about 185°C. NMR spectrum: 0,65 (d (i II II : 5β2)1,
20 (t l 6 II : -N(CH,CH,)
, )1.40 (d l 311", -CH-CH
,) 1.70 (8 width 14 II: -CH(CH,
)2-CH2N: )2,65 (q H47/:
-N(CH,-CH,), )3.50 (dd;
1.7J: 5ε2)7.6s (g width; lH:=C
μ-5-)7.85 (ddHllll:1'll,) From the following components, 5δ-(5-diethylamine bent-2-
il) thiomethylene pristinamycin IA (product A
A 10% aqueous solution of AP) was obtained: Product AAP 0.05 g 0.1 #i acid 0.5 QC N,N-)ethyl-4-acetylthiopencun-1-amine (4,0 g) and 5-diethylaminopentane-2-thiol can be prepared similarly to the method described in Application Example 22 for preparing 3-dimethylamino-2-methylpropanethiol, except starting from sodium (0046F). Ta. “Flash” chromatography [eluent: ethyl acetate/methanol (7o/a O
capacity)) and fractions 16-24e
After concentration to dryness, 5-diethylaminopentane-2-thiol (2.0 g) was obtained as a yellow oil. N,N-)ethyl-4-chloropentan-1-amine (
Similar to the method described in Application Example 22 for the preparation of N,N-dimethyl-3-acetylthio-2-methylprobylamine, but starting from N.32I) and thiol acetic acid (15.2 g). N-diethyl-4-acetylthiopentan-1-amine could be prepared. This gave the product (4,a 1g) as a yellow oil. N,N-diethyl-4-chloropencun-1-amine is disclosed in US Pat. No. 2,432 by M, S, KHARASH and C,F, FUCH5. It could be prepared by the method described in '905. Application Example 37 149-5δ-[(4
-)f-ruphenyl)sulfonyloxymethylene]pristinamycin IA (7,617) solution at -10°C.
It was cooled to a certain temperature. 2-dimethylaminoethanol (2-dimethylaminoethanol) in tetrahydrone (6 occ) to which was added a 50% dispersion of sodium hydride in mineral oil (0,3511).
0.651) was gradually added to the initial solution while maintaining the temperature. When the addition was complete, the temperature was gradually increased to about 20°C. The reaction mixture was stirred at this temperature for 24 hours, then diluted with methylene chloride (500 cc) and washed with a saturated solution of ammonium chloride (2×50 cc). The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure (2, TkPa) at 40°C. The resulting residue was subjected to "flash" chromatography [eluent: chloroform/methanol (9515
volume)]. 150-2 Sections 12 to 17 are brought together and heated under reduced pressure (2,
The mixture was concentrated to dryness at 25° C. and 7 kPa). This results in approximately 16
It formed as a beige powder which melted at 0°C. NMR spectrum: 0.65 (dd: 111: 5β!)2,3
(a H6II: -N(C41,), )2.65
(tLpl 2H knee C1l, N\) 3.42 (dd
IIH: 5g, ) 4.15 (2 OCH, -) 5.15 (
d ll ) I : 5 II ) 7.45 (under aromatic proton; IH:\ 7C=CIIO-) 7.80 (dd i 111: 1 'H6) From the following components, 5δ in the hydrochloride state -(2-dimethylaminoethoxymethylene)pristinamycin IA (product AA
A 1% aqueous solution of Q) was obtained: Product AAQ O,031 0,IN Hydrochloric acid 0.3 cc Distilled water Sufficient amount to make 3 mice Application Example 3B 4-Amino-1-methylpiperidine (o, 12Il) in ethanol (2ace) at a temperature of about 20℃.
It was added to a solution of (4-methylphenyl)sulfonyloxymethine/pristinamycin s A (0.5 g). After stirring at this temperature for 16 hours, the reaction mixture was diluted with methylene chloride (toocc) and twice with distilled water (toocc).
Washed in total (Iooec). The organic phase was dried over sodium sulfate and then dried under reduced pressure (2,
7k Pα) at 30°C. The residue was stirred with ethyl ether (15 CC). Filtered through, 5δ-(1
-Methylpiperidin-4-yl) aminomethylenepristinamycin I A (0,429) was obtained in the form of a white powder, the characteristics of which were identical to those described in application example 14. 4-amino-1-methylpiperidine was able to be prepared at 11M as shown in Application Example 14. Application Example 39 5δ-(1-methylpiperidin-4-yl)aminomethylenepristinamycin IA (described in Application Example 14)
1-Amine of Application Example 14” below), and 5δ-(3-dimethylamino/propyl)thiomethylenepristinamycin IA as described in Application Example 20 (shown below as [
The thiol of Application Example 20) was applied to Example 3,
5,6°8.10,11,12,13,14,15,2
1. Prepared from the products of general formula (1) described in 22 and 24. The operating conditions are shown in the following table: 153- = 82; - In human therapy, the products of the general formula (l) are particularly useful in the treatment of infections caused by bacteria. Depending on the duration; for adults, between 200 and 4000 η per day is generally administered parenterally, especially subcutaneously with gradual perfusion.In general, the doctor will determine the age, weight and subject to be treated. will determine the dosage that is considered most appropriate as a function of all other factors specific to the patient. Patent Applicant Lorne-Bouland-Saint 155- 154-

Claims (1)

[Claims] In the formula, Y represents hydrogen or dimethylamino, and R is a) hydrogen or hydroxyl; , each of which is hydrogen, phenyl or pyridyl, unsubstituted or substituted in the straight or branched chain by a sialkylamide group having 1 to 4 carbon atoms in the alkyl moiety, straight or branched. having from 1 to 10 carbon atoms in the branched chain and is unsubstituted or substituted with hydroxyl, mercapto, carboxyl, pyrinol or anilino, or at least one alkyl is itself substituted with hydroxyl and mercapto with anilino. Alkylamino °
or dialkylamino-substituted alkyl, alkenyl of 3 or 4 carbon atoms, or alkynyl of 3 or 4 carbon atoms, or R1 and R22- taken together with the nitrogen atom to which they are attached, forms a 5- or 6-shell heterocyclic ring optionally substituted with an alkyl group, or represents a (-) halogen atom, a trimethylsilyloxy or dialkylphosphoryloxy group, or a group of the formula % formula % ); R3 is alkyl, trifluoromethyl or trichloromethyl or unsubstituted;
or phenyl substituted with halogen, or alkyl or nitro, and R1 is defined as R3, or alkylcarbonylethyl, 2-
represents alkylcarbonylethyl, alkoxycarbonylmethyl, 2-alkoxycarbonylethyl or alkoxy, and unless otherwise specified, the alkyl moiety or group in "-" is linear or branched if L< is containing 1 to 1 of sinernostin, its isomers if present and mixtures thereof, and its salts, its metal salts and its nitrogen chlorine (Sl 2, R is hydrogen, hydroxyl or a group of the formula -NR,R,, where R3 and R2 each represent hydrogen, phenyl, dialkylaminophenyl, alkyl, hydroxyl,
Synergystine according to claim 1, which represents alkyl substituted with mercapto, carbonyl, pyridyl, anilino, hydroxyalkylamino or [hydroxylalkyl)amine, or represents alkynyl of 3 to 4 carbon atoms. . 3. Sinernstin according to claim 1, which is δ-dimethylaminomethylene pristinamycin A and its acid salt. . Synergystin according to claim 4, which is 4.5δ-dimethylaminomethylenevirginiamycin S and its acid addition salt. 5. Synerdi'stin of claim 1, which is j3δ-methylenepristinamycin IA and its acid addition salt. 6, 5δ-1 = droxymethylene pristinamycin I
8 and its acid f=1 salt, according to claim 1. Synergystin according to claim 1, which is 7.5δ-methylenevirginiamycin S and its acid addition salt. 1i0 In the formula, R1 and R2 are each an alkyl group having 1 to 4 carbon atoms, or together with the nitrogen atom to which they are bonded, R1 and R2 are 5 or 6 alkyl groups optionally substituted with an alkyl group. and Xl and X2 may be the same or different from each other, and each represents alkoxy or
A compound represented by the following formula -NR, which represents a substituted ami7 group defined in the same manner as R2, is reacted with a compound represented by the following formula, in which Y is as defined in claim 1. , R, and R2 are as defined above, i.e., a compound of formula, optionally following the reaction of is reacted with an alkali metal borohydride in the presence of a strong substitute acid to produce a compound as described in paragraph 1, in which R represents a hydrogen atom: 71 and R2, in which R'1 and R'2 are defined above, except for the meanings given above).
or 3) reacting with an amine having the definition given by to form a compound according to claim 1, in which R is defined analogously to -NR', 17'2; or 3) said formation. is hydrolyzed to form a compound of the formula in which Y is as defined in claim 1, and then, if appropriate, the resulting raw 8-acid is treated with a halogenating agent or In the formula, l('1.f, l-lymethylsilyloxy, dialkylphosphoryloxy or the formula -03O,, R3 or 10 C(-) defined in the first aspect of the claims
[<, and X represents the halokene radical J'-, wherein R is defined in C) on page J of Claim 1. Claim 1 consisting of converting the compound as described, optionally separating the product obtained into its isomers (if any), and optionally converting this product into its salt. The method for producing synergystin as described.